Amino-quinolines as kinase inhibitors

ABSTRACT

Disclosed are compounds having the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , R 3  and Z are as defined herein, and methods of making and using the same.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 4-amino-quinolines that inhibit RIP2kinase and methods of making and using the same. Specifically, thepresent invention relates to substituted 4-amino-quinolines as RIP2kinase inhibitors.

2. Background of the Invention

Receptor interacting protein-2 (RIP2) kinase, which is also referred toas CARD3, RICK, CARDIAK, or RIPK2, is a TKL family serine/threonineprotein kinase involved in innate immune signaling. RIP2 kinase iscomposed of an N-terminal kinase domain and a C-terminalcaspase-recruitment domain (CARD) linked via an intermediate (IM) region((1998) J. Biol. Chem. 273, 12296-12300; (1998) Current Biology 8,885-889; and (1998) J. Biol. Chem. 273, 16968-16975). The CARD domain ofRIP2 kinase mediates interaction with other CARD-containing proteins,such as NOD1 and NOD2 ((2000) J. Biol. Chem. 275, 27823-27831 and (2001)EMBO reports 2, 736-742). NOD1 and NOD2 are cytoplasmic receptors whichplay a key role in innate immune surveillance. They recognize both grampositive and gram negative bacterial pathogens and are activated byspecific peptidoglycan motifs, diaminopimelic acid (i.e., DAP) andmuramyl dipeptide (MDP), respectively ((2007) J Immunol 178, 2380-2386).

Following activation, RIP2 kinase associates with NOD 1 or NOD2 andappears to function principally as a molecular scaffold to bringtogether other kinases (TAK1, IKKα/β/γ) involved in NF-κB andmitogen-activated protein kinase activation ((2006) Nature ReviewsImmunology 6, 9-20). RIP2 kinase undergoes a K63-linkedpolyubiquitination on lysine-209 which facilitates TAK1 recruitment((2008) EMBO Journal 27, 373-383). This post-translational modificationis required for signaling as mutation of this residue prevents NOD1/2mediated NF-kB activation. RIP2 kinase also undergoesautophosphorylation on serine-176, and possibly other residues ((2006)Cellular Signalling 18, 2223-2229). Studies using kinase dead mutants(K47A) and non-selective small molecule inhibitors have demonstratedthat RIP2 kinase activity is important for regulating the stability ofRIP2 kinase expression and signaling ((2007) Biochem J404, 179-190 and(2009) J. Biol. Chem. 284, 19183-19188).

Dysregulation of RIP2-dependent signaling has been linked toautoinflammatory diseases. Gain-of-function mutations in theNACHT-domain of NOD2 cause Blau Syndrome, early-onset sarcoidosis, apediatric granulomateous disease characterized by uveitis, dermatitis,and arthritis ((2001) Nature Genetics 29, 19-20; (2005) Journal ofRheumatology 32, 373-375; (2005) Current Rheumatology Reports 7,427-433; (2005) Blood 105, 1195-1197; (2005) European Journal of HumanGenetics 13, 742-747; (2006) American Journal of Ophthalmology 142,1089-1092; (2006) Arthritis & Rheumatism 54, 3337-3344; (2009) Arthritis& Rheumatism 60, 1797-1803; and (2010) Rheumatology 49, 194-196).Mutations in the LRR-domain of NOD2 have been strongly linked tosusceptibility to Crohn's Disease ((2002) Am. J. Hum. Genet. 70,845-857; (2004) European Journal of Human Genetics 12, 206-212; (2008)Mucosa/Immunology (2008) 1 (Suppl 1), S5-S9. 1, S5-S9; (2008)Inflammatory Bowel Diseases 14, 295-302; (2008) Experimental Dermatology17, 1057-1058; (2008) British Medical Bulletin 87, 17-30; (2009)Inflammatory Bowel Diseases 15, 1145-1154 and (2009) Microbes andInfection 11, 912-918). Mutations in NOD1 have been associated withasthma ((2005) Hum. Mol. Genet. 14, 935-941) and early-onset andextra-intestinal inflammatory bowel disease ((2005) Hum. Mol. Genet. 14,1245-1250). Genetic and functional studies have also suggested a rolefor RIP2-dependent signaling in a variety of other granulomateousdisorders, such as sarcoidosis ((2009) Journal of Clinical Immunology29, 78-89 and (2006) Sarcoidosis Vasculitis and Diffuse Lung Diseases23, 23-29) and Wegner's Granulomatosis ((2009) Diagnostic Pathology 4,23).

A potent, selective, small molecule inhibitor of RIP2 kinase activitywould block RIP2-dependent pro-inflammatory signaling and therebyprovide a therapeutic benefit in autoinflammatory diseases characterizedby increased and/or dysregulated RIP2 kinase activity.

SUMMARY OF THE INVENTION

The invention is directed to 6,7-disubstituted-4-amino-quinolines.Specifically, the invention is directed to a compound according toFormula (I):

wherein:

R¹ is H, —SO₂(C₁-C₄alkyl), —CO(C₁-C₄alkyl), or (C₁-C₄alkyl);

R² is —SOR^(a) or —SO₂R^(a), wherein R^(a) is an optionally substituted(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 4-7 membered heterocycloalkyl, aryl, orheteroaryl group, wherein:

said (C₁-C₆)alkyl is optionally substituted by one or two groups eachindependently selected from the group consisting of cyano, hydroxyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl,—SO₂(C₁-C₄ alkyl), —CONH₂, —CONH(C₁-C₄ alkyl), —NHC(═O)(C₁-C₄ alkyl),—CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C(═O)(C₁-C₄ alkyl)),—SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHSO₂(C₁-C₄ alkyl), —SO₂N(C₁-C₄alkyl)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(SO₂(C₁-C₄ alkyl)), amino, (C₁-C₄alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, C₃-C₇cycloalkyl, phenyl,5-6 membered heteroaryl, 9-10 membered heteroaryl, 4-7 memberedheterocycloalkyl and (phenyl)(C₁-C₄ alkyl)amino-, wherein saidC₃-C₇cycloalkyl, phenyl, (phenyl)(C₁-C₄ alkyl)amino-, 5-6 memberedheteroaryl, 9-10 membered heteroaryl or 4-7 membered heterocycloalkyl isoptionally substituted by 1-3 groups each independently selected fromthe group consisting of halogen, —CF₃, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyland (C₁-C₄)alkoxy,

said (C₃-C₇)cycloalkyl or 4-7 membered heterocycloalkyl is optionallysubstituted by 1-3 groups each independently selected from the groupconsisting of halogen, —CF₃, hydroxyl, amino, (C₁-C₄ alkyl)amino-,(C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl-, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₂-C₄)alkoxy-, and

said aryl or heteroaryl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl-and (C₁-C₄)alkoxy,

and wherein said heteroaryl is a 5-6 membered heteroaryl or a 9-10membered heteroaryl, and any of said 4-7 membered heterocycloalkylcontains one heteroatom selected from the group consisting of N, O andS, any of said 5-6 membered heteroaryl contains one heteroatom selectedfrom the group consisting of N, O and S and optionally furthercontaining one or two nitrogen atoms, and any of said 9-10 memberedheteroaryl contains one heteroatom selected from the group consisting ofN, O and S and optionally further containing 1, 2 or 3 nitrogen atoms;

R³ is halogen, hydroxy, (C₁-C₄)alkyl-, (C₁-C₄)alkoxy-,halo(C₁-C₄)alkyl-, halo(C₁-C₄)alkoxy-, (C₁-C₄)alkoxy(C₁-C₆)alkyl-, halo(C₁-C₄)alkoxy(C₁-C₆)alkyl-, (C₁-C₄)alkoxy(C₂-C₆)alkoxy-,halo(C₁-C₄)alkoxy(C₂-C₆)alkoxy-, hydroxy(C₁-C₄)alkyl-,hydroxy(C₂-C₆)alkoxy-, cyano(C₁-C₄)alkyl-, cyano(C₂-C₆)alkoxy-, or(C₃-C₆)cycloalkoxy-, wherein the halo(C₁-C₄)alkyl-, halo(C₁-C₄)alkoxy-,halo(C₁-C₄)alkoxy(C₁-C₆)alkyl-, orhalo(C₁-C₄)alkoxy(C₂-C₆)alkoxy-contains 2 or 3 halo atoms and whereinthe (C₃-C₆)cycloalkyl moiety of the (C₃-C₆)cycloalkoxy- group, isoptionally substituted by a group selected from the group consisting ofcyano, halo, hydroxyl, (C₁-C₆)alkoxy and (C₁-C₄)alkoxy(C₂-C₆)alkoxy;

Z is phenyl or aryl(C₁-C₄)alkyl-, substituted by R⁴, R⁵, R⁶ and R⁷,wherein:

R⁴ is H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

each of R⁵, R⁶ and R⁷ is independently selected from the groupconsisting of H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; or

Z is phenyl substituted by R⁸, R⁹ and R¹⁰, wherein:

R⁸ and R⁹ are located on adjacent atoms and taken together with theatoms to which they are attached form a 5-membered heterocyclic groupcontaining 1, 2 or 3 heteroatoms each independently selected from thegroup consisting of N, O and S, which 5-membered heterocyclic group issubstituted by R¹¹;

wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

the other of R¹⁰ or R¹¹ is H, hydroxyl, halogen, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; or

Z is pyrazolyl, having the formula:

wherein:

R¹² is methyl or trifluoromethyl (—CH₃ or —CF₃);

R¹³ is H, methyl, hydroxymethyl, or trifluoromethyl (—CH₃, —CH₂OH or—CF₃);

R¹⁴ is H or (C₁-C₃)alkyl; or

R¹² and R¹³, taken together with the atoms to which they are attached,form a 6 membered carbocyclic ring or heterocyclic ring substituted byR¹⁵ and R¹⁶, wherein the heterocyclic ring contains 1 nitrogen atom;

wherein R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, and aminocarbonyl, wherein the phenyl moiety ofsaid phenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy;

provided that the compound is notN-(4-chloro-2-fluorophenyl)-7-methoxy-6-[(2-methoxyethyl)sulfinyl]-4-quinolinamineor 3-[[7-bromo-6-(methylsulfonyl)-4-quinolinyl]amino]-4-methyl-phenol;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The compounds according to Formula (I), or salts, particularlypharmaceutically acceptable salts, thereof, are inhibitors of RIP2kinase.

Accordingly, the present invention is also directed to a method ofinhibiting RIP2 kinase which method comprises contacting a cell with acompound according to Formula (I), or a salt, particularly apharmaceutically acceptable salt, thereof.

The invention is further directed to a method of treating a RIP2kinase-mediated disease or disorder which comprises administering atherapeutically effective amount of a compound according to Formula (I),or a salt, particularly a pharmaceutically acceptable salt thereof, to apatient (a human or other mammal, particularly, a human) in needthereof. Examples of RIP2 kinase-mediated diseases or disorders includeuveitis, Crohn's disease, ulcerative colitis, early-onset andextra-intestinal inflammatory bowel disease and granulomateousdisorders, such as sarcoidosis, Blau syndrome, early-onset sarcoidosisand Wegner's Granulomatosis.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound according to Formula (I), or a salt,particularly a pharmaceutically acceptable salt, thereof and apharmaceutically acceptable excipient. Particularly, this invention isdirected to a pharmaceutical composition for the treatment of a RIP2kinase-mediated disease or disorder, where the composition comprises acompound according to Formula (I), or a salt, particularly apharmaceutically acceptable salt, thereof and a pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the combined cytokine response in rat whole blood samplesobtained after pre-dosing rats with the compound of Example 1, followedby dosing with L18-MDP.

FIG. 2 shows the combined cytokine response in rat whole blood samplesobtained after pre-dosing rats with the compound of Example 5, followedby dosing with L18-MDP.

FIG. 3 shows the IL-8 cytokine response in rat whole blood samplesobtained after pre-dosing rats with the compound of Example 23, followedby dosing with L18-MDP.

FIG. 4 shows the IL-8 cytokine response in rat whole blood samplesobtained after pre-dosing rats with the compound of Example 31, followedby dosing with L18-MDP.

DETAILED DESCRIPTION OF THE INVENTION

The alternative definitions for the various groups and substituentgroups of Formula (I) provided throughout the specification are intendedto particularly describe each compound species disclosed herein,individually, as well as groups of one or more compound species. Thescope of this invention includes any combination of these group andsubstituent group definitions. The compounds of the invention are onlythose which are contemplated to be “chemically stable” as will beappreciated by those skilled in the art.

It will also be appreciated by those skilled in the art that when Z ispyrazolyl, the compounds of this invention may exist as pyrazole isomersrepresented by Formula (I-A) and Formula (I-B):

When R¹⁴ is H, the compounds of this invention may exist as tautomers(I-A) and (I-B) and may be represented as Formula (I-C).

When R¹⁴ is (C₁-C₃)alkyl, the compounds of this invention, may exist aseither one of the regioisomers represented by Formula (I-A) or Formula(I-B), or as a mixture thereof.

In addition, it will be appreciated by those skilled in the art that thecompounds of this invention, depending on further substitution, mayexist in other tautomeric forms. All tautomeric forms of the compoundsdescribed herein are intended to be encompassed within the scope of thepresent invention. It is to be understood that any reference to a namedcompound of this invention is intended to encompass all tautomers of thenamed compound and any mixtures of tautomers of the named compound.

As used herein, the term “alkyl” represents a saturated, straight orbranched hydrocarbon moiety. Exemplary alkyls include, but are notlimited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl,s-butyl, isobutyl, t-butyl and pentyl. The term “C₁-C₄ alkyl” refers toan alkyl group or moiety containing from 1 to 4 carbon atoms.

When the term “alkyl” is used in combination with other substituentgroups, such as “haloalkyl” or “hydroxyalkyl” or “arylalkyl”, the term“alkyl” is intended to encompass a divalent straight or branched-chainhydrocarbon radical. For example, “arylalkyl” is intended to mean theradical-alkylaryl, wherein the alkyl moiety thereof is a divalentstraight or branched-chain carbon radical and the aryl moiety thereof isas defined herein, and is represented by the bonding arrangement presentin a benzyl group (—CH₂-phenyl); “halo(C₁-C₄)alkyl” or“(C₁-C₄)haloalkyl” is intended to mean a radical having one or morehalogen atoms, which may be the same or different, at one or more carbonatoms of an alkyl moiety containing from 1 to 4 carbon atoms, which a isstraight or branched-chain carbon radical, and is represented by atrifluoromethyl group (—CF₃).

As used herein, the term “cycloalkyl” refers to a non-aromatic,saturated, cyclic hydrocarbon ring. The term “(C₃-C₈)cycloalkyl” refersto a non-aromatic cyclic hydrocarbon ring having from three to eightring carbon atoms. Exemplary “(C₃-C₈)cycloalkyl” groups useful in thepresent invention include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

“Alkoxy” refers to a group containing an alkyl radical attached throughan oxygen linking atom. The term “(C₁-C₄)alkoxy” refers to a straight-or branched-chain hydrocarbon radical having at least 1 and up to 4carbon atoms attached through an oxygen linking atom. Exemplary“(C₁-C₄)alkoxy” groups useful in the present invention include, but arenot limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,s-butoxy, isobutoxy, and t-butoxy.

“Aryl” represents a group or moiety comprising an aromatic, monovalentmonocyclic or bicyclic hydrocarbon radical containing from 6 to 10carbon ring atoms, which may be fused one or more cycloalkyl rings.

Generally, in the compounds of this invention, aryl is phenyl.

Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.

“Heterocycloalkyl” represents a group or moiety comprising anon-aromatic, monovalent monocyclic or bicyclic radical, which issaturated or partially unsaturated, containing 3 to 10 ring atoms,unless otherwise specified, which includes 1 to 4 heteroatoms selectedfrom nitrogen, oxygen and sulfur. Illustrative examples ofheterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl,pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl,tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl),dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl,dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl,azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and1,5,9-triazacyclododecyl.

In some of the compounds of this invention, heterocycloalkyl groupsinclude 4-membered heterocycloalkyl groups containing one heteroatom,such as oxetanyl, thietanyl and azetidinyl.

In other compounds of this invention, heterocycloalkyl groups include5-membered heterocycloalkyl groups containing one heteroatom selectedfrom nitrogen, oxygen and sulfur and optionally containing one or two anadditional nitrogen atoms, or optionally containing one additionaloxygen or sulfur atom, such as pyrrolidyl (or pyrrolidinyl),tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl,oxazolinyl, thiazolinyl, imidazolinyl, pyrazolinyl, 1,3-dioxolanyl, and1,3-oxathiolan-2-on-yl.

In other compounds of this invention, heterocycloalkyl groups are6-membered heterocycloalkyl groups containing one heteroatom selectedfrom nitrogen, oxygen and sulfur and optionally containing one or two anadditional nitrogen atoms or one additional oxygen or sulfur atom, suchas piperidyl (or piperidinyl), piperazinyl, morpholinyl,thiomorpholinyl, 1,1 dioxoido-thiomorpholin-4-yl, tetrahydropyranyl,dihydropyranyl, tetrahydro-2H-1,4-thiazinyl, 1,4-dioxanyl,1,3-oxathianyl, and 1,3-dithianyl.

“Heteroaryl” represents a group or moiety comprising an aromaticmonovalent monocyclic or bicyclic radical, containing 5 to 10 ringatoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. This term also encompasses bicyclic heterocyclic-aryl compoundscontaining an aryl ring moiety fused to a heterocycloalkyl ring moiety,containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selectedfrom nitrogen, oxygen and sulfur. Illustrative examples of heteroarylsinclude, but are not limited to, thienyl, pyrrolyl, imidazolyl,pyrazolyl, furyl (or furanyl), isothiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl,benzo[b]thienyl, isobenzofuryl, 2,3-dihydrobenzofuryl, chromenyl,chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl,benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl,pteridinyl, and isothiazolyl.

In some embodiments, the heteroaryl groups present in the compounds ofthis invention are 5-membered and/or 6-membered monocyclic heteroarylgroups. Selected 5-membered heteroaryl groups contain one nitrogen,oxygen or sulfur ring heteroatom, and optionally contain 1, 2 or 3additional nitrogen ring atoms. Selected 6-membered heteroaryl groupscontain 1, 2, 3 or 4 nitrogen ring heteroatoms. Selected 5- or6-membered heteroaryl groups include thienyl, pyrrolyl, imidazolyl,pyrazolyl, furyl (furanyl), isothiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, thiazolyl, triazolyl and tetrazolyl or pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl and triazinyl.

In other embodiments, the heteroaryl groups present in the compounds ofthis invention are 9-membered or 10-membered monocyclic heteroarylgroups. Selected 9-10 membered heteroaryl groups contain one nitrogen,oxygen or sulfur ring heteroatom, and optionally contain 1, 2, 3 or 4additional nitrogen ring atoms.

In some of the compounds of this invention, heteroaryl groups include9-membered heteroaryl groups include benzothienyl, benzofuranyl,indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, indolizinyl,isobenzofuryl, 2,3-dihydrobenzofuryl, benzoxazolyl, benzthiazolyl,benzimidazolyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl,1,3-benzoxathiol-2-on-yl (2-oxo-1,3-benzoxathiolyl), purinyl andimidazopyridinyl.

In some of the compounds of this invention, heteroaryl groups include10-membered heteroaryl groups include chromenyl, chromanyl, quinolyl,isoquinolyl, phthalazinyl, naphthridinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, tetrahydroquinolinyl, cinnolinyl, and pteridinyl.

It is to be understood that the terms heterocycle, heterocyclic,heteroaryl, heterocycloalkyl, are intended to encompass stableheterocyclic groups where a ring nitrogen heteroatom is optionallyoxidized (e.g., heterocyclic groups containing an N-oxide, such aspyridine-N-oxide) or where a ring sulfur heteroatom is optionallyoxidized (e.g., heterocyclic groups containing sulfones or sulfoxidemoieties, such as tetrahydrothienyl-1-oxide (a tetrahydrothienylsulfoxide) or tetrahydrothienyl-1,1-dioxide (a tetrahydrothienylsulfone)).

“Oxo” represents a double-bonded oxygen moiety; for example, if attacheddirectly to a carbon atom forms a carbonyl moiety (C═O). The terms“halogen” and “halo” represent chloro, fluoro, bromo or iodosubstituents. “Hydroxy” or “hydroxyl” is intended to mean the radical—OH.

As used herein, the terms “compound(s) of the invention” or “compound(s)of this invention” mean a compound of Formula (I), as defined above, inany form, i.e., any salt or non-salt form (e.g., as a free acid or baseform, or as a salt, particularly a pharmaceutically acceptable saltthereof) and any physical form thereof (e.g., including non-solid forms(e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous orcrystalline forms, specific polymorphic forms, solvate forms, includinghydrate forms (e.g., mono-, di- and hemi-hydrates)), and mixtures ofvarious forms.

As used herein, the term “optionally substituted” means unsubstitutedgroups or rings (e.g., cycloalkyl, heterocycloalkyl, and heteroarylrings) and groups or rings substituted with one or more specifiedsubstituents.

The invention is further directed to a compound according to Formula(I), wherein:

W is H, —SO₂(C₁-C₄alkyl), —CO(C₁-C₄alkyl), or (C₁-C₄alkyl);

R² is —SOR^(a) or —SO₂R^(a), wherein R^(a) is an optionally substituted(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 4-7 membered heterocycloalkyl, aryl, orheteroaryl, wherein:

said (C₁-C₆)alkyl is optionally substituted by one or two groups eachindependently selected from the group consisting of cyano, hydroxyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl,—SO₂(C₁-C₄ alkyl), —CONH₂, —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₄ alkyl),amino, (C₁-C₄ alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-,C₃-C₇cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 memberedheteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C₁-C₄alkyl)amino-, wherein said C₃-C₇cycloalkyl, phenyl, (phenyl)(C₁-C₄alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy,

said (C₃-C₇)cycloalkyl or 4-7 membered heterocycloalkyl is optionallysubstituted by 1-3 groups each independently selected from the groupconsisting of halogen, —CF₃, hydroxyl, amino, (C₁-C₄)alkyl,phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl-, oxo and (C₁-C₄)alkoxy, and

said aryl or heteroaryl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl-and (C₁-C₄)alkoxy,

and wherein said heteroaryl is a 5-6 membered heteroaryl or a 9-10membered heteroaryl, and any of said 4-7 membered heterocycloalkylcontains one heteroatom selected from the group consisting of N, O andS, any of said 5-6 membered heteroaryl contains one heteroatom selectedfrom the group consisting of N, O and S and optionally furthercontaining one or two nitrogen atoms, and any of said 9-10 memberedheteroaryl contains one heteroatom selected from the group consisting ofN, O and S and optionally further containing 1, 2 or 3 nitrogen atoms;

R³ is halogen, hydroxy, (C₁-C₄)alkyl-, (C₁-C₄)alkoxy-,halo(C₁-C₄)alkyl-, halo(C₁-C₄)alkoxy-, (C₁-C₄)alkoxy(C₁-C₆)alkyl-, halo(C₁-C₄)alkoxy(C₁-C₆)alkyl-, (C₁-C₄)alkoxy(C₂-C₆)alkoxy-,halo(C₁-C₄)alkoxy(C₂-C₆)alkoxy-, hydroxy(C₁-C₄)alkyl-,hydroxy(C₂-C₆)alkoxy-, cyano(C₁-C₄)alkyl-, cyano(C₂-C₆)alkoxy-, or(C₃-C₆)cycloalkoxy-, wherein the halo(C₁-C₄)alkyl-, halo(C₁-C₄)alkoxy-,halo(C₁-C₄)alkoxy(C₁-C₆)alkyl-, or halo(C₁-C₄)alkoxy(C₂-C₆)alkoxy-contains 2 or 3 halo atoms and wherein the (C₃-C₆)cycloalkyl moiety ofthe (C₃-C₆)cycloalkoxy- group, is optionally substituted by a groupselected from the group consisting of cyano, halo, hydroxyl,(C₁-C₆)alkoxy and (C₁-C₄)alkoxy(C₂-C₆)alkoxy;

Z is phenyl or aryl(C₁-C₄)alkyl-, substituted by R⁴, R⁵, R⁶ and R⁷,wherein:

R⁴ is H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

each of R⁵, R⁶ and R⁷ is independently selected from the groupconsisting of H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; or

Z is phenyl substituted by R⁸, R⁹ and R¹⁰, wherein:

R⁸ and R⁹ are located on adjacent atoms and taken together with theatoms to which they are attached form a 5-membered heterocyclic groupcontaining 1, 2 or 3 heteroatoms each independently selected from thegroup consisting of N, O and S, which 5-membered heterocyclic group issubstituted by R¹¹;

wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

the other of R¹⁰ or R¹¹ is H, hydroxyl, halogen, —CF₃,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; or

Z is pyrazolyl, having the formula:

wherein:

R¹² is methyl or trifluoromethyl (—CH₃ or —CF₃);

R¹³ is H, methyl or trifluoromethyl (—CH₃ or —CF₃);

R¹⁴ is H or (C₁-C₃)alkyl; or

R¹² and R¹³, taken together with the atoms to which they are attached,form a 6 membered carbocyclic ring or heterocyclic ring substituted byR¹⁵ and R¹⁶, wherein the heterocyclic ring contains 1 nitrogen atom;

wherein R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, and aminocarbonyl, wherein the phenyl moiety ofsaid phenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy;

provided that the compound is notN-(4-chloro-2-fluorophenyl)-7-methoxy-6-[(2-methoxyethyl)sulfinyl]-4-quinolinamineor 3-[[7-bromo-6-(methylsulfonyl)-4-quinolinyl]amino]-4-methyl-phenol(See WO 98/13350 and Bioorg. Med. Chem. Lett. (2007), 17(21),5886-5893);

or a salt, particularly a pharmaceutically acceptable salt, thereof.

In one embodiment of this invention, R¹ is H. In other embodiments, R¹is —SO₂(C₁-C₄alkyl) or —CO(C₁-C₄alkyl); specifically, —SO₂CH₃ or —COCH₃.In other embodiments, R¹ is (C₁-C₂)alkyl; specifically, —CH₃. Inspecific embodiments, R¹ is H or —CH₃; generally, R¹ is H.

In another embodiment, R² is —SOR^(a). In yet another embodiment, R² is—SO₂R^(a).

In a further embodiment, R^(a) is (C₁-C₆)alkyl, C₃-C₆cycloalkyl,4-6-membered heterocycloalkyl, 5-6-membered heteroaryl or phenyl;

wherein said (C₁-C₆)alkyl is optionally substituted by for 2substituents each independently selected from the group consisting ofhydroxyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino, (C₁-C₄alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, (phenyl)(C₁-C₄alkyl)amino-, —CO₂(C₁-C₄)alkyl, —CONH₂, —SO₂(C₁-C₄)alkyl, and aC₃-C₆cycloalkyl, phenyl, 4-6-membered heterocycloalkyl, 5-6-memberedheteroaryl, or 9-10-membered heteroaryl, where said C₃-C₆cycloalkyl,phenyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, or9-10-membered heteroaryl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl-and (C₁-C₄)alkoxy; and

wherein said C₃-C₆cycloalkyl, 4-6-membered heterocycloalkyl,5-6-membered heteroaryl or phenyl is optionally substituted by 1-3groups each independently selected from the group consisting of halogen,—CF₃, hydroxyl, amino, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy.

In a further embodiment, R^(a) is (C₁-C₆)alkyl, wherein said(C₁-C₆)alkyl is optionally substituted by for 2 substituents eachindependently selected from the group consisting of hydroxyl,(C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino, (C₁-C₄ alkyl)amino-,(C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, (phenyl)(C₁-C₄ alkyl)amino-,—CO₂(C₁-C₄)alkyl, —CONH₂, —SO₂(C₁-C₄)alkyl, and a C₃-C₆cycloalkyl,phenyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, or9-10-membered heteroaryl, where said C₃-C₆cycloalkyl, phenyl,4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, or 9-10-memberedheteroaryl is optionally substituted by 1-3 groups each independentlyselected from the group consisting of halogen, —CF₃, hydroxyl, amino,(C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and(C₁-C₄)alkoxy.

In a further embodiment, R^(a) is C₃-C₆cycloalkyl, 4-6-memberedheterocycloalkyl, 5-6-membered heteroaryl or phenyl, wherein saidC₃-C₆cycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroarylor phenyl is optionally substituted by 1-3 groups each independentlyselected from the group consisting of halogen, —CF₃, hydroxyl, amino,(C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and(C₁-C₄)alkoxy.

When R^(a) is a heterocycloalkyl or heteroaryl group, it is to beunderstood that the heterocycloalkyl or heteroaryl group is bonded tothe sulfur atom of the —SOR^(a) or —SO₂R^(a) moiety by a ring carbonatom.

In a still further embodiment, R^(a) is (C₁-C₄)alkyl, wherein said(C₁-C₄)alkyl is optionally substituted by for 2 substituents eachindependently selected from the group consisting of hydroxyl,(C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃ alkyl)amino-,(C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-, C₃-C₆cycloalkyl (optionallysubstituted by (C₁-C₄)alkyl or hydroxy(C₁-C₄)alkyl), 4-6-memberedheterocycloalkyl (optionally substituted by (C₁-C₄)alkyl), 5-6-memberedheteroaryl (optionally substituted by (C₁-C₄)alkyl), phenyl, or9-10-membered heteroaryl.

In a still further embodiment, R^(a) is C₃-C₆cycloalkyl, 4-6-memberedheterocycloalkyl, 5-6-membered heteroaryl or phenyl, wherein:

said C₃-C₆cycloalkyl is optionally substituted by for 2 substituentseach independently selected from the group consisting of hydroxyl,(C₁-C₄)alkyl, (C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃alkyl)amino-, and (C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-, said 4-6-memberedheterocycloalkyl is optionally substituted by 1 or 2 groupsindependently selected from the group consisting of (C₁-C₄)alkyl orbenzyl, wherein the 4-6 membered heterocycloalkyl contains oneheteroatom selected from the group consisting of N, O and S,

said 5-6-membered heteroaryl is optionally substituted by (C₁-C₄)alkylor hydroxy(C₁-C₄)alkyl, wherein the 5-6 membered heteroaryl contains oneheteroatom selected from the group consisting of N, O and S or containsone nitrogen atom and a second one heteroatom selected from the groupconsisting of N, O and S optionally contains additional heteroatomnitrogen atom, and

said phenyl is optionally substituted by amino.

In a still further embodiment, R^(a) is (C₁-C₄)alkyl wherein said(C₁-C₄)alkyl is optionally substituted by for 2 substituents eachindependently selected from the group consisting of hydroxyl,(C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃ alkyl)amino-,(C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-, C₃-C₆cycloalkyl (optionallysubstituted by (C₁-C₄)alkyl or hydroxy(C₁-C₄)alkyl), 4-6-memberedheterocycloalkyl (optionally substituted by (C₁-C₄)alkyl), 5-6-memberedheteroaryl (optionally substituted by (C₁-C₄)alkyl), phenyl, and9-10-membered heteroaryl.

In a still further embodiment, R^(a) is (C₁-C₄)alkyl wherein said(C₁-C₄)alkyl is optionally substituted by a substituent selected fromthe group consisting of hydroxyl, (C₁-C₂)alkoxy,(C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃ alkyl)amino-, and (C₁-C₃alkyl)(C₁-C₂ alkyl)amino-.

In a still further embodiment, R^(a) is C₃-C₆cycloalkyl wherein saidC₃-C₆cycloalkyl is optionally substituted by for 2 substituents eachindependently selected from the group consisting of hydroxyl,(C₁-C₄)alkyl, (C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃alkyl)amino-, and (C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-.

In a still further embodiment, R^(a) is 4-6-membered heterocycloalkylwherein said 4-6-membered heterocycloalkyl is optionally substituted by1 or 2 groups independently selected from the group consisting of(C₁-C₄)alkyl or benzyl, wherein the 4-6 membered heterocycloalkylcontains one heteroatom selected from the group consisting of N, O andS.

In a still further embodiment, R^(a) is 5-6 membered heterocycloalkyloptionally substituted by 1 or 2 independently selected (C₁-C₄)alkylgroups, wherein the 5-6 membered heterocycloalkyl contains oneheteroatom selected from the group consisting of N, O and S. In specificembodiments, the optionally substituted 5-6 membered heterocycloalkylcontains one oxygen heteroatom.

In a still further embodiment, R^(a) is 5-6-membered heteroaryl whereinsaid 5-6-membered heteroaryl is optionally substituted by (C₁-C₄)alkylor hydroxy(C₁-C₄)alkyl, wherein the 5-6 membered heteroaryl contains oneheteroatom selected from the group consisting of N, O and S or containsone nitrogen atom and a second heteroatom selected from the groupconsisting of N, O and S and optionally contains one additional nitrogenatom. In a still further embodiment, R^(a) is 6-membered heteroaryloptionally substituted by (C₁-C₄)alkyl or hydroxy(C₁-C₄)alkyl, whereinthe 6 membered heteroaryl contains one or two nitrogen atoms.

In a still further embodiment, R^(a) is phenyl, wherein said phenyl isoptionally substituted by amino.

In a still further embodiment, R^(a) is a 5-6-membered heterocycloalkyl,wherein said 5-6-membered heterocycloalkyl is optionally substituted by1 or 2 independently selected (C₁-C₄)alkyl groups; wherein the 5-6membered heterocycloalkyl group contains 1 heteroatom selected from thegroup consisting of N, O and S.

In a still further embodiment, R^(a) is (C₁-C₄)alkyl, tetrahydrofuranyl,tetrahydropyranyl or piperidinyl, wherein:

said (C₁-C₄)alkyl is optionally substituted by a substituent selectedfrom the group consisting of hydroxyl, (C₁-C₂)alkoxy,(C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃ alkyl)amino-, (C₁-C₃alkyl)(C₁-C₂ alkyl)amino-, and a C₃-C₆cycloalkyl (optionally substitutedby (C₁-C₄)alkyl or hydroxy(C₁-C₄)alkyl), and

said tetrahydrofuranyl, tetrahydropyranyl or piperidinyl is optionallysubstituted by 1 or 2 groups independently selected from the groupconsisting of halogen, —CF₃, hydroxyl, amino, (C₁-C₄)alkyl,phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy.

In another embodiment, R^(a) is an unsubstituted (C₁-C₄)alkyl or a(C₁-C₄)alkyl substituted by a substituent selected from the groupconsisting of hydroxyl, (C₁-C₂)alkoxy, and (C₁-C₂)alkoxy(C₂-C₃)alkoxy-.In yet another embodiment, R^(a) is tetrahydropyranyl, wherein thetetrahydropyranyl group is optionally substituted by 1 or 2independently selected (C₁-C₄)alkyl groups. In still another embodiment,R^(a) is tetrahydrofuranyl, wherein the tetrahydrofuranyl group isoptionally substituted by 1 or 2 independently selected (C₁-C₄)alkylgroups. In still another embodiment, R^(a) is piperidinyl, wherein thepiperidinyl group is optionally substituted by 1 or 2 independentlyselected (C₁-C₄)alkyl groups.

In specific embodiments, R^(a) is —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂OH,—C(CH₃)₂CH₂OH, —CH₂CH₂OCH₃, tetrahydro-2H-pyran-4-yl,2,2-dimethyltetrahydro-2H-pyran-4-yl, 4-methyltetrahydro-2H-pyran-4-yl,(3R,4R)-3-methyltetrahydro-2H-pyran-4-yl, or(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl.

In selected embodiments, R^(a) is —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂OH,or tetrahydro-2H-pyran-4-yl. In other specific embodiments, R^(a) is—CH₂CH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OH, tetrahydrofuran-3-yl, or1-methyl-piperidin-4-yl-.

In another embodiment, R³ is halogen, hydroxy, (C₁-C₄)alkyl-,halo(C₁-C₄)alkyl-, (C₁-C₄)alkoxy-, halo(C₁-C₄)alkoxy-,(C₁-C₄)alkoxy(C₁-C₆)alkyl-, (C₁-C₄)alkoxy(C₂-C₆)alkoxy-,hydroxy(C₁-C₄)alkyl-, or hydroxy(C₂-C₆)alkoxy-. In yet anotherembodiment, R³ is halogen, hydroxy, (C₁-C₄)alkyl-, halo(C₁-C₄)alkyl-,(C₁-C₄)alkoxy-, (C₁-C₄)alkoxy(C₁-C₆)alkyl-, (C₁-C₄)alkoxy(C₂-C₆)alkoxy-,hydroxy(C₁-C₄)alkyl-, or hydroxy(C₂-C₆)alkoxy-. In a further embodiment,R³ is halogen, hydroxy, (C₁-C₃)alkyl-, halo(C₁-C₂)alkyl-,(C₁-C₃)alkoxy-, halo(C₁-C₃)alkoxy-, (C₁-C₃)alkoxy(C₁-C₃)alkyl-,(C₁-C₃)alkoxy(C₂-C₃)alkoxy-, hydroxy(C₁-C₃)alkyl-, orhydroxy(C₂-C₃)alkoxy-. In a further embodiment, R³ is halogen, hydroxy,(C₁-C₃)alkyl-, halo(C₁-C₂)alkyl-, (C₁-C₃)alkoxy-,(C₁-C₃)alkoxy(C₁-C₃)alkyl-, (C₁-C₃)alkoxy(C₂-C₃)alkoxy-,hydroxy(C₁-C₃)alkyl-, or hydroxy(C₂-C₃)alkoxy-. In a selectedembodiment, R³ is chloro, bromo, methyl, ethyl, trifluoromethyl,hydroxy, methoxy, difluoromethoxy, ethoxy, or 2-hydroxyethoxy-. In aspecific embodiment, R³ is chloro, bromo, methyl, ethyl,trifluoromethyl, hydroxy, methoxy, ethoxy or hydroxyethoxy-.

In another embodiment, Z is phenyl or phenyl(C₁-C₄)alkyl-, wherein anyphenyl (including the phenyl moiety of phenyl(C₁-C₄)alkyl-) issubstituted by R⁴, R⁵, R⁶ and R⁷ wherein:

R⁴ is H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl- oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

each of R⁵, R⁶ and R⁷ is independently selected from the groupconsisting of H, hydroxyl, halogen, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl and (C₁-C₄)alkoxy.

Specifically, Z is phenyl, substituted by 1, 2 or 3 substituents eachindependently selected from the group consisting of hydroxyl, halogen,—CF₃, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl and (C₁-C₄)alkoxy.

More specifically, Z is phenyl, having the formula:

wherein:

R^(Z1) is H, halogen, —CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; particularly,R^(Z1) is H or methyl;

R^(Z2) is H, halogen, —CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

R^(Z3) is H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, wherein the phenyl moiety ofsaid phenoxy or phenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

R^(Z4) is hydroxyl, hydroxy(C₁-C₄)alkyl or (C₁-C₄)alkoxy. In a morespecific embodiment, Z is 3-methoxy-4-chloro-phenyl or2-methyl-5-(hydroxymethyl)-phenyl.

In yet another embodiment, Z is phenyl substituted by R⁸, R⁹ and R¹⁰,wherein:

R⁸ and R⁹ are located on adjacent atoms and taken together with theatoms to which they are attached form a 5-membered heterocyclic groupcontaining 1, 2 or 3 heteroatoms each independently selected from thegroup consisting of N, O and S, which 5-membered heterocyclic group issubstituted by R¹¹;

wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl, —CF₃,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy, and the other of R¹⁰ orR¹¹ is H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or(C₁-C₄)alkoxy.

Specifically, Z is benzothiazolyl, optionally substituted by for 2substituents each independently selected from the group consisting ofhalogen, (C₁-C₄)alkyl, —CF₃, and (C₁-C₄)alkoxy. More specifically, Z isan optionally substituted benzothiazol-6-yl optionally substituted bychloro, fluoro, —CF₃, methyl, or methoxy. In a specific embodiment, Z isbenzothiazol-6-yl.

In yet another embodiment, Z is pyridyl substituted by R⁸, R⁹ and R¹⁰,wherein:

R⁸ and R⁹ are located on adjacent atoms and taken together with theatoms to which they are attached form a 5-membered heterocyclic groupcontaining 1, 2 or 3 heteroatoms each independently selected from thegroup consisting of N, O and S, which 5-membered heterocyclic group issubstituted by R¹¹;

wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl, —CF₃,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy and the other of R¹⁰ orR¹¹ is H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or(C₁-C₄)alkoxy.

In another embodiment, Z is pyrazolyl, R¹² is methyl or trifluoromethyl,R¹³ is H, methyl, or trifluoromethyl, and R¹⁴ is H or methyl. In afurther embodiment, Z is pyrazolyl, R¹² and R¹³ are independentlyselected from the group consisting of methyl and trifluoromethyl, andR¹⁴ is H or methyl. In a specific embodiment, Z is pyrazolyl, R¹² ismethyl, R¹³ is methyl or trifluoromethyl, and R¹⁴ is H.

In a still further embodiment, Z is pyrazolyl, substituted by R¹² andR¹³ wherein:

R¹² and R¹³ are located on adjacent carbon atoms and taken together withthe atoms to which they are attached form a 6 membered carbocyclic ringor heterocyclic ring substituted by R¹⁵ and R¹⁶;

wherein R¹⁵ is H, halogen, cyano, (C₁-C₄)alkyl, —CF₃, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

R¹⁶ is H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or(C₁-C₄)alkoxy.

In another embodiment, the invention is directed to a compound accordingto Formula (I), wherein Z is a 9-membered bi-cyclic heteroaryl group,wherein the 9-membered bi-cyclic heteroaryl group is an optionallysubstituted indazolyl or pyrazolo[3,4-b]pyridinyl, bonded to thequinolyl-amino (NR¹) moiety via a substitutable carbon ring atom of the5-membered (pyrazolyl) ring moiety of the indazolyl orpyrazolo[3,4-b]pyridinyl group, wherein the indazolyl orpyrazolo[3,4-b]pyridinyl is substituted on the 6-membered (phenyl orpyridyl) ring moiety thereof by 1 or 2 substituents each independentlyselected from the group consisting of hydroxyl, halogen, —CF₃,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl and (C₁-C₄)alkoxy, or a salt,particularly a pharmaceutically acceptable salt, thereof.

In a further embodiment, Z is an optionally substituted indazolyl orpyrazolo[3,4-b]pyridinyl group, where the Z group is optionallysubstituted by 1 or 2 substituents each independently selected from thegroup consisting of chloro, fluoro, methyl, and methoxy. In specificembodiments, Z is 4-chloro-1H-indazol-3-yl, 5-chloro-1H-indazol-3-yl,6-chloro-1H-indazol-3-yl, 7-chloro-1H-indazol-3-yl,5-fluoro-1H-indazol-3-yl, 7-fluoro-1H-indazol-3-yl,5-,7-difluoro-1H-indazol-3-yl, 6,7-difluoro-1H-indazol-3-yl,5-methoxy-1H-indazol-3-yl or 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl.

In another embodiment, the invention is directed to a compound accordingto Formula (II):

or a salt, particularly a pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R¹² and R¹³ are as defined herein.

In another embodiment, the invention is directed to method of inhibitingRIP2 kinase comprising contacting the kinase with a compound accordingto Formula (III):

or a salt, particularly a pharmaceutically acceptable salt thereof,wherein R¹, R² and R³ are as defined herein, and

R^(Z1) is H, halogen, —CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; particularly,R^(Z1) is H

R^(Z2) is H, H halogen, —CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

R^(Z3) is H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, wherein the phenyl moiety ofsaid phenoxy or phenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

R^(Z4) is hydroxyl, hydroxy(C₁-C₄)alkyl or (C₁-C₄)alkoxy.

In a compound, or salt thereof, of Formula (I), (II) and (III):

R¹ is H;

R² is —SOR^(a), or —SO₂R^(a), and R^(a) is (C₁-C₄)alkyl or a5-6-membered heterocycloalkyl, wherein said (C₁-C₄)alkyl is optionallysubstituted by a substituent selected from the group consisting ofhydroxyl, (C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃alkyl)amino-, and (C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-, and said5-6-membered heterocycloalkyl is optionally substituted by 1 or 2independently selected (C₁-C₄)alkyl groups, wherein the 5-6 memberedheterocycloalkyl group contains 1 heteroatom selected from the groupconsisting of N, O and S; and

R³ is halogen, hydroxy, (C₁-C₃)alkyl-, halo(C₁-C₂)alkyl-,(C₁-C₃)alkoxy-, (C₁-C₃)alkoxy(C₁-C₃)alkyl-, (C₁-C₃)alkoxy(C₂-C₃)alkoxy-,hydroxy(C₁-C₃)alkyl-, or hydroxy(C₂-C₃)alkoxy-.

In a compound, or salt thereof, of Formula (I), (II) and (III):

R¹ is H;

R² is —SOR^(a), or —SO₂R^(a), and R^(a) is —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH₂CH₂OH, or tetrahydro-2H-pyran-4-yl; and

R³ is chloro, bromo, methyl, ethyl, trifluoromethyl, hydroxy, methoxy orethoxy. In a compound, or salt thereof, of Formula (I), (II) and (III):

R¹ is H;

R² is —SOR^(a), or —SO₂R^(a), and R^(a) is —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH₂CH₂OH, —C(CH₃)₂CH₂OH, —CH₂CH₂OCH₃, tetrahydro-2H-pyran-4-yl,2,2-dimethyltetrahydro-2H-pyran-4-yl, 4-methyltetrahydro-2H-pyran-4-yl,(3R,4R)-3-methyltetrahydro-2H-pyran-4-yl, or(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl; and

R³ is chloro, bromo, methyl, ethyl, trifluoromethyl, hydroxy, methoxy,difluoromethoxy, ethoxy, or 2-hydroxyethoxy-.

In one embodiment of a compound, or salt thereof, of Formula (I), asdefined above, Z is 3-methoxy-4-chloro-phenyl or2-methyl-5-(hydroxymethyl)-phenyl.

In another embodiment of a compound, or salt thereof, of Formula (I), asdefined above, Z is pyrazolyl, R¹² is methyl, R¹³ is methyl ortrifluoromethyl, and R¹⁴ is H.

In yet another embodiment of a compound, or salt thereof, of Formula(I), as defined above, Z is benzothiazol-6-yl.

In still another embodiment of a compound, or salt thereof, of Formula(I), as defined above, Z is 4-chloro-1H-indazol-3-yl,5-chloro-1H-indazol-3-yl, 6-chloro-1H-indazol-3-yl,7-chloro-1H-indazol-3-yl, 5-fluoro-1H-indazol-3-yl,7-fluoro-1H-indazol-3-yl, 5-,7-difluoro-1H-indazol-3-yl,6,7-difluoro-1H-indazol-3-yl, 5-methoxy-1H-indazol-3-yl or5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl.

Specific compounds of this invention are:

-   6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfinyl)-4-quinolinamine;-   6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine;-   2-((4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-7-methoxyquinolin-6-yl)sulfonyl)-2-methylpropan-1-ol;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   2-((4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-7-methylquinolin-6-yl)sulfonyl)ethanol;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)-7-methoxyquinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((2-methoxyethyl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)-7-methoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-methoxyquinolin-4-amine;-   N-[4-chloro-3-(methyloxy)phenyl]-6-[(1,1-dimethyl    ethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;-   N-[4-chloro-3-(methyloxy)phenyl]-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4-quinolinamine;-   N-1,3-benzothiazol-5-yl-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4-quinolinamine;-   2-{[4-{[4-chloro-3-(methyloxy)phenyl]amino}-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol;-   N-(5-fluoro-1H-indazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4-quinolinamine;-   2-{[4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol;-   N-[4-chloro-3-(methyloxy)phenyl]-6-[(1-methylethyl)    sulfonyl]-7-(methyloxy)-4-quinolinamine;-   N-1,3-benzothiazol-5-yl-6-[(1-methylethyl)    sulfonyl]-7-(methyloxy)-4-quinolinamine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-[(1-methylethyl)    sulfonyl]-7-(methyloxy)-4-quinolinamine;-   N-(5-fluoro-1H-indazol-3-yl)-6-[(1-methylethyl)    sulfonyl]-7-(methyloxy)-4-quinolinamine;-   2-{[4-(1,3-benzothiazol-5-ylamino)-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol;-   6-(isopropylsulfonyl)-7-methoxy-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)quinolin-4-amine;-   6-(tert-butylsulfonyl)-7-methoxy-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)quinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-7-ethoxy-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine;-   7-chloro-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   7-chloro-N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(5-fluoro-1H-indazol-3-yl)-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)-7-(trifluoromethyl)    quinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-(trifluoromethyl)quinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-7-chloro-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine;-   6-(tert-butylsulfonyl)-7-ethyl-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine;-   N-(5-fluoro-1H-indazol-3-yl)-6-(isopropylsulfonyl)-7-methylquinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-(isopropylsulfonyl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethylquinolin-4-amine;-   7-ethyl-N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   (3-(6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methylphenyl)methanol;-   7-ethoxy-N-(5-fluoro-1H-indazol-3-yl)-6-(isopropylsulfonyl)quinolin-4-amine;-   N-(7-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(7-fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5,7-difluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(6,7-difluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(7-chloro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;-   6-(tert-butylsulfonyl)-7-methoxy-N-(5-methoxy-1H-indazol-3-yl)quinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(7-fluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5,7-difluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(5-methoxy-1H-indazol-3-yl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(6,7-difluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;-   6-(tert-butylsulfonyl)-N-(7-chloro-1H-indazol-3-yl)-7-methylquinolin-4-amine;-   7-methoxy-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(5,7-difluoro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(6-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(6,7-difluoro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   7-methoxy-N-(5-methoxy-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(5-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(7-chloro-1H-indazol-3-yl)-7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-1,3-benzothiazol-5-yl-6-(methylsulfonyl)-4-quinolinamine;-   7-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   7-bromo-6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine;-   7-bromo-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   7-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-(isopropylsulfonyl)quinolin-4-amine;-   7-bromo-N-(5-fluoro-1H-indazol-3-yl)-6-(isopropylsulfonyl)quinolin-4-amine;-   7-bromo-N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;-   6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-ol;-   2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-yl)oxy)ethanol;-   6-(tert-butylsulfonyl)-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine;-   7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethanol;-   (3-(6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazol-5-yl)methanol;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(5-fluoro-1H-indazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   7-ethyl-N-(5-fluoro-1H-indazol-3-yl)-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(7-chloro-1H-indazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

Selected compounds of this invention are:

-   6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine;-   6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-yl)oxy)ethanol;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

Particular compounds of this invention are:

-   6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;-   N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;    specifically,    6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

Representative compounds of this invention are provided in Examples1-83.

Accordingly, a compound of the invention includes a compound of Formula(I), particularly, a compound of Formula (I), (II) or (III) and thespecific compounds described herein, or a salt thereof, particularly apharmaceutically acceptable salt thereof. In one embodiment, theinvention is directed to a method of inhibiting RIP2 kinase comprisingcontacting a cell with a compound of the invention. In anotherembodiment, the invention is directed to a method of treating a RIP2kinase-mediated disease or disorder comprising administering atherapeutically effective amount of a compound of the invention to ahuman in need thereof. The invention is still further directed to theuse of a compound of the invention or a pharmaceutical compositioncomprising a compound of the invention to inhibit RIP2 kinase and/ortreat a RIP2 kinase-mediated disease or disorder.

The compounds according to Formula (I) may contain one or moreasymmetric center (also referred to as a chiral center) and may,therefore, exist as individual enantiomers, diastereomers, or otherstereoisomeric forms, or as mixtures thereof. Chiral centers, such as achiral carbon, or particularly, a chiral —SO— moiety, may also bepresent in the compounds of this invention. Where the stereochemistry ofa chiral center present in a compound of this invention, or in anychemical structure illustrated herein, is not specified the structure isintended to encompass all individual stereoisomers and all mixturesthereof. For example, each of(R)-6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamineand(S)-6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamineare encompassed by6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine.Thus, compounds according to Formula (I) containing one or more chiralcenter may be used as racemic mixtures, enantiomerically enrichedmixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula (I) whichcontain one or more asymmetric center may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. The skilled artisan willappreciate that where the desired stereoisomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired form. Alternatively,specific stereoisomers may be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

It is to be understood that a solid form of a compound of the inventionmay exist in crystalline forms, non-crystalline forms or a mixturethereof. Such crystalline forms may also exhibit polymorphism (i.e. thecapacity to occur in different crystalline forms). These differentcrystalline forms are typically known as “polymorphs.” Polymorphs havethe same chemical composition but differ in packing, geometricalarrangement, and other descriptive properties of the crystalline solidstate. Polymorphs, therefore, may have different physical propertiessuch as shape, density, hardness, deformability, stability, anddissolution properties. Polymorphs typically exhibit different meltingpoints, IR spectra, and X-ray powder diffraction patterns, which may beused for identification. One of ordinary skill in the art willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the conditions used incrystallizing/recrystallizing the compound.

Because of their potential use in medicine, the salts of the compoundsof Formula (I) are preferably pharmaceutically acceptable salts.Suitable pharmaceutically acceptable salts include those described byBerge, Bighley and Monkhouse J. Pharm. Sci (1977) 66, pp 1-19. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention.

When a compound of the invention is a base (contains a basic moiety), adesired salt form may be prepared by any suitable method known in theart, including treatment of the free base with an inorganic acid, suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, and the like, or with a pyranosidyl acid, such asglucuronic acid or galacturonic acid, or with an alpha-hydroxy acid,such as citric acid or tartaric acid, or with an amino acid, such asaspartic acid or glutamic acid, or with an aromatic acid, such asbenzoic acid or cinnamic acid, or with a sulfonic acid, such asp-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or thelike.

Suitable addition salts are formed from acids which form non-toxic saltsand examples include acetate, p-aminobenzoate, ascorbate, aspartate,benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate,bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate,clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate,esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate,gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide,hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, monopotassium maleate, mucate, napsylate, nitrate,N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmate,palmitate, pantothenate, phosphate/diphosphate, pyruvate,polygalacturonate, propionate, saccharate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate,triethiodide, trifluoroacetate and valerate.

Other exemplary acid addition salts include pyrosulfate, sulfite,bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, suberate, sebacate,butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,phenylacetate, phenylpropionate, phenylbutrate, lactate,γ-hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate,propanesulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate.

If an inventive basic compound is isolated as a salt, the correspondingfree base form of that compound may be prepared by any suitable methodknown to the art, including treatment of the salt with an inorganic ororganic base, suitably an inorganic or organic base having a higherpK_(a) than the free base form of the compound.

When a compound of the invention is an acid (contains an acidic moiety),a desired salt may be prepared by any suitable method known to the art,including treatment of the free acid with an inorganic or organic base,such as an amine (primary, secondary, or tertiary), an alkali metal oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids such asglycine and arginine, ammonia, primary, secondary, and tertiary amines,and cyclic amines, such as N-methyl-D-glucamine, diethylamine,isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine,ethanolamine, piperidine, morpholine, and piperazine, as well asinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, and lithium.

Certain of the compounds of the invention may form salts with one ormore equivalents of an acid (if the compound contains a basic moiety) ora base (if the compound contains an acidic moiety). The presentinvention includes within its scope all possible stoichiometric andnon-stoichiometric salt forms.

Compounds of the invention having both a basic and acidic moiety may bein the form of zwitterions, acid-addition salt of the basic moiety orbase salts of the acidic moiety.

This invention also provides for the conversion of one pharmaceuticallyacceptable salt of a compound of this invention, e.g., a hydrochloridesalt, into another pharmaceutically acceptable salt of a compound ofthis invention, e.g., a sulfate salt.

For solvates of the compounds of Formula (I), including solvates ofsalts of the compounds of Formula (I), that are in crystalline form, theskilled artisan will appreciate that pharmaceutically acceptablesolvates may be formed wherein solvent molecules are incorporated intothe crystalline lattice during crystallization. Solvates may involvenonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid,ethanolamine, and EtOAc, or they may involve water as the solvent thatis incorporated into the crystalline lattice. Solvates wherein water isthe solvent that is incorporated into the crystalline lattice aretypically referred to as “hydrates.” Hydrates include stoichiometrichydrates as well as compositions containing variable amounts of water.The invention includes all such solvates, particularly hydrates. It isto be understood that the term “a salt, particularly a pharmaceuticallyacceptable salt, thereof, or hydrate thereof” encompasses a salt of acompound of Formula (I), a pharmaceutically acceptable salt of acompound of Formula (I), a hydrate of a compound of Formula (I), ahydrate of a salt of a compound of Formula (I), and a hydrate of apharmaceutically acceptable salt of a compound of Formula (I).

Because the compounds of Formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

General Synthetic Methods

The compounds of Formula (I) may be obtained by using syntheticprocedures illustrated in the Schemes below or by drawing on theknowledge of a skilled organic chemist. The syntheses provided in theseSchemes are applicable for producing compounds of the invention having avariety of different substituent groups employing appropriateprecursors, which are suitably protected if needed, to achievecompatibility with the reactions outlined herein. Subsequentdeprotection, where needed, affords compounds of the nature generallydisclosed. While the Schemes are shown with compounds only of Formula(I), they are illustrative of processes that may be used to make thecompounds of the invention.

Intermediates (compounds used in the preparation of the compounds of theinvention) may also be present as salts. Thus, in reference tointermediates, the phrase “compound(s) of formula (number)” means acompound having that structural formula or a pharmaceutically acceptablesalt thereof.

The compounds of this invention may be particularly useful for treatmentof RIP2 kinase-mediated diseases or disorders, particularly, uveitis,interleukin-1 converting enzyme (ICE, also known as Caspase-1)associated fever syndrome, dermatitis, acute lung injury, type 2diabetes mellitus, arthritis (specifically rheumatoid arthritis),inflammatory bowel disorders (such as ulcerative colitis and Crohn'sdisease), early-onset and extra-intestinal inflammatory bowel disease,prevention of ischemia reperfusion injury in solid organs (specificallykidney) in response ischemia induced by cardiac surgery, organtransplant, sepsis and other insults, liver diseases (non-alcoholsteatohepatitis, alcohol steatohepatitis, and autoimmune hepatitis),allergic diseases (such as asthma), transplant reactions (such as graftversus host disease), autoimmune diseases (such as systemic lupuserythematosus, and multiple sclerosis), and granulomateous disorders(such as sarcoidosis, Blau syndrome, early-onset sarcoidosis, Wegner'sgranulomatosis, and interstitial pulmonary disease).

The compounds of this invention may be particularly useful in thetreatment of uveitis, ICE fever, Blau Syndrome, early-onset sarcoidosis,ulcerative colitis, Crohn's disease, Wegener's granulamatosis andsarcoidosis.

Treatment of RIP2 kinase-mediated diseases or disorders, or morebroadly, treatment of immune mediated diseases including, but notlimited to, allergic diseases, autoimmune diseases, prevention oftransplant rejection and the like, may be achieved using a compound ofthis invention as a monotherapy, or in dual or multiple combinationtherapy, particularly for the treatment of refractory cases, such as incombination with other anti-inflammatory and/or anti-TNF agents, whichmay be administered in therapeutically effective amounts as is known inthe art.

For example, the compounds of this invention may be administered incombination with corticosteroids and/or anti-TNF agents to treat Blausyndrome, early-onset sarcoidosis; or in combination with anti-TNFbiologics or other anti-inflammatory biologics to treat Crohn's Disease;or in combination with 5-ASA (mesalamine) or sulfasalazine to treatulcerative colitis; or in combination with low-dose corticosteroidsand/or methotrexate to treat Wegener's granulamatosis or sarcoidosis orinterstitial pulmonary disease; or in combination with a biologic (e.g.anti-TNF, anti-IL-6, etc.) to treat rheumatoid arthritis; or incombination with anti-IL6 and/or methotrexate to treat ICE fever.

Examples of suitable anti-inflammatory agents include corticosteroids,particularly low-dose corticosteroids (such as Deltasone® (prednisone))and anti-inflammatory biologics (such as Acterma® (anti-IL6R mAb) andRituximab® (anti-CD20 mAb)). Examples of suitable anti-TNF agentsinclude anti-TNF biologics (such as Enbrel® (etanecerpt)), Humira®(adalimumab), Remicade® (infliximab) and Simponi® (golimumab)).

This invention also provides a compound of Formula (I), or a saltthereof, particularly a pharmaceutically acceptable salt thereof, foruse in therapy, specifically for use in the treatment of a RIP2kinase-mediated disease or disorder, for example the diseases anddisorders recited herein.

The invention also provides the use of a compound of Formula (I), or asalt thereof, particularly a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for use in the treatment of a RIP2kinase-mediated disease or disorder, for example the diseases anddisorders recited herein.

A therapeutically “effective amount” is intended to mean that amount ofa compound that, when administered to a patient in need of suchtreatment, is sufficient to effect treatment, as defined herein. Thus,e.g., a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is a quantity of aninventive agent that, when administered to a human in need thereof, issufficient to modulate or inhibit the activity of RIP2 kinase such thata disease condition which is mediated by that activity is reduced,alleviated or prevented. The amount of a given compound that willcorrespond to such an amount will vary depending upon factors such asthe particular compound (e.g., the potency (pIC₅₀), efficacy (EC₅₀), andthe biological half-life of the particular compound), disease conditionand its severity, the identity (e.g., age, size and weight) of thepatient in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art. Likewise, the duration oftreatment and the time period of administration (time period betweendosages and the timing of the dosages, e.g., before/with/after meals) ofthe compound will vary according to the identity of the mammal in needof treatment (e.g., weight), the particular compound and its properties(e.g., pharmaceutical characteristics), disease or disorder and itsseverity and the specific composition and method being used, but cannevertheless be determined by one of skill in the art.

“Treating” or “treatment” is intended to mean at least the mitigation ofa disease condition in a patient. The methods of treatment formitigation of a disease condition include the use of the compounds inthis invention in any conventionally acceptable manner, for example forprevention, retardation, prophylaxis, therapy or cure of a mediateddisease or disorder. Specific diseases and disorders that may beparticularly susceptible to treatment using a compound of this inventionare described herein.

The compounds of the invention may be administered by any suitable routeof administration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration, rectaladministration, and administration by inhalation. Parenteraladministration refers to routes of administration other than enteral,transdermal, or by inhalation, and is typically by injection orinfusion. Parenteral administration includes intravenous, intramuscular,and subcutaneous injection or infusion. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. Topical administration includesapplication to the skin.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the disease ordisorder being treated, the severity of the disease or disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.

For use in therapy, the compounds of the invention will be normally, butnot necessarily, formulated into a pharmaceutical composition prior toadministration to a patient. Accordingly, the invention also is directedto pharmaceutical compositions comprising a compound of the inventionand a pharmaceutically acceptable excipient.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein an effective amount of a compound of theinvention can be extracted and then given to the patient such as withpowders, syrups, and solutions for injection. Alternatively, thepharmaceutical compositions of the invention may be prepared andpackaged in unit dosage form. For oral application, for example, one ormore tablets or capsules may be administered. A dose of thepharmaceutical composition contains at least a therapeutically effectiveamount of a compound of this invention (i.e., a compound of Formula (I),or a salt, particularly a pharmaceutically acceptable salt, thereof).When prepared in unit dosage form, the pharmaceutical compositions maycontain from 1 mg to 1000 mg of a compound of this invention.

The pharmaceutical compositions of the invention typically contain onecompound of the invention. However, in certain embodiments, thepharmaceutical compositions of the invention contain more than onecompound of the invention. In addition, the pharmaceutical compositionsof the invention may optionally further comprise one or more additionalpharmaceutically active compounds.

As used herein, “pharmaceutically acceptable excipient” means amaterial, composition or vehicle involved in giving form or consistencyto the composition. Each excipient must be compatible with the otheringredients of the pharmaceutical composition when commingled such thatinteractions which would substantially reduce the efficacy of thecompound of the invention when administered to a patient andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically acceptable are avoided. In addition, each excipientmust of course be of sufficiently high purity to render itpharmaceutically acceptable.

The compounds of the invention and the pharmaceutically acceptableexcipient or excipients will typically be formulated into a dosage formadapted for administration to the patient by the desired route ofadministration. Conventional dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols and solutions;and (6) topical administration such as creams, ointments, lotions,solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound or compounds ofthe invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anti-caking agents, humectants, chelating agents, plasticizers,viscosity increasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising an effective amount of a compoundof the invention and a diluent or filler. Suitable diluents and fillersinclude lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.corn starch, potato starch, and pre-gelatinized starch), cellulose andits derivatives (e.g. microcrystalline cellulose), calcium sulfate, anddibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

Names for the intermediate and final compounds described herein weregenerated using a software naming program. It will be appreciated bythose skilled in the art that in certain instances this program willname a structurally depicted compound as a tautomer of that compound. Itis to be understood that any reference to a named compound or astructurally depicted compound is intended to encompass all tautomers ofsuch compounds and any mixtures of tautomers thereof.

In the following experimental descriptions, the following abbreviationsmay be used:

Abbreviation Meaning AcOH acetic acid aq aqueous brine saturated aqueousNaCl CH₂Cl₂, DCM methylene chloride CH₃CN or MeCN acetonitrile CH₃NH₂methylamine d day DCE 1,2-dichloroethane DMA dimethyl acetamide DMFN,N-dimethylformamide DMSO dimethylsulfoxide EDC1-ethyl-3-(3-dimethylaminopropyl) carbodiimide equiv equivalents Etethyl Et₃N triethylamine Et₂O or DME diethyl ether EtOAc ethyl acetateEtOH ethanol h, hr hour HATU O-(7-Azabenzotriazol-1yl)-N,N,N′,N′-tetramethylyronium hexafluorophosphate HCl hydrochloric acid HMPAhexamethylphosphoramide IPA isopropyl alcohol i-Pr₂NEtN′,N′-diisopropylethylamine KOt-Bu potassium tert-butoxide LDA lithiumdiisopropyl amide LCMS liquid chromatography-mass spectroscopy LHDMSlithium hexamethyldisilazane Me methyl MeI Methyl iodide MeOH or CH₃OHmethanol MgSO₄ magnesium sulfate min minute MP-carbonate resin polymerbound tetraalkylammonium carbonate MS mass spectrum μw microwave NaBH₄sodium borohydride Na₂CO₃ sodium carbonate NaHCO₃ sodium bicarbonateNaOH sodium hydroxide Na₂SO₄ sodium sulfate NH₄Cl ammonium chlorideNiCl₂•6H₂O nickel (II) chloride hexahydrate NMP N-methyl-2-pyrrolidonePh phenyl RBF round bottomed flask rt room temperature satd or sat'dsaturated SCX strong cation exchange SPE solid phase extraction TLC Thinlayer chromatography TFA trifluoroacetic acid THF tetrahydrofuran t_(R)retention time

Preparation 1 6-bromo-4-chloro-7-(methyloxy)quinoline

Step 1.5-({[4-bromo-3-(methyloxy)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione:2,2-dimethyl-1,3-dioxane-4,6-dione (8.5 g, 58 mmol) in trimethylorthoformate (50 mL, 450 mmol) was refluxed at 105° C. for 1 hr.4-Bromo-3-methoxyaniline (10.5 g, 50.4 mmol) was then added andrefluxing was continued for and additional hour. The suspension wasfiltered, and the solid was washed with MeOH and vacuum dried to yield5-({[4-bromo-3-(methyloxy)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(17 g, 49 mmol, 96% yield). ¹H NMR (400 MHz, DMSO-d) δ ppm 1.68 (s, 6H),3.90 (s, 3H), 7.11 (dd, J=8.6 Hz, 2 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 7.59(d, J=8.6 Hz, 1H), 8.64 (s, 1H), 11.23 (br. s., 1H).

Step 2. 6-bromo-7-(methyloxy)-4-quinolinol: To diphenyl ether (68 mL,420 mmol) at 230° C. was added5-({[4-bromo-3-(methyloxy)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(15 g, 42 mmol), and the mixture was stirred for 1 hr. The reactionmixture was poured into hexane after being cooled to room temperature.The precipitate was filtered and washed with hexane. The brown solid wasdried under vacuum overnight to afford6-bromo-7-(methyloxy)-4-quinolinol (10 g, 33 mmol, 79% yield). ¹H NMR(400 MHz, DMSO-d) δ ppm 3.94 (s, 3H), 5.99 (dd, J=7.4 Hz, 1.2 Hz, 1H),7.05 (s, 1H), 7.86 (dd, J=7.4 Hz, 5.8 Hz, 1H), 8.16 (s, 1H), 11.68 (br.s., 1H). MS (m/z) 254, 256 (M+H⁺).

Step 3. 6-bromo-4-chloro-7-(methyloxy)quinoline:6-bromo-7-(methyloxy)-4-quinolinol (4.17 g, 16.41 mmol) in phosphorusoxychloride (7.73 mL, 82 mmol) was stirred at 110° C. for 1 hr. Thereaction mixture was cooled and slowly poured into saturated sodiumcarbonate with ice while stirring. The resulting suspension wasfiltered, the solid was rinsed with water and vacuum-dried overnight toyield 6-bromo-4-chloro-7-(methyloxy)quinoline (4.6 g, 16 mmol, 97%yield). ¹H NMR (400 MHz, DMSO-d) δ ppm 4.05 (s, 3H), 7.61 (s, 1H), 7.65(d, J=4.8 Hz, 1H), 8.38 (s, 1H), 8.81 (d, J=4.8 Hz, 1H). MS (m/z) 272,274 (M+H⁺).

The following intermediates can be made in an analogous manner:

Preparation 26-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine

A mixture of 6-bromo-4-chloro-7-(methyloxy)quinoline (0.42 g, 1.5 mmol)and 4,5-dimethyl-1H-pyrazol-3-amine (0.17 g, 1.5 mmol) was heated inEtOH (3 mL) at 80° C. in a sealed tube for 16 h. The reaction mixturewas cooled and Et₂O (10 mL) was added. Precipitate6-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinaminewas filtered and dried to give a brown solid. ¹H NMR (DMSO-d₆) δ ppm12.63 (br. s., 1H), 10.42 (br. s., 1H), 9.10 (s, 1H), 8.47 (d, J=7.1 Hz,1H), 7.47 (s, 1H), 6.71 (d, J=6.8 Hz, 1H), 4.06 (s, 3H), 2.23 (s, 3H),1.85 (s, 3H); MS (m/z) 347, 349 (M+H⁺).

The following compounds were made in an analogous manner. Isopropanolmay be used as the solvent in addition to ethanol.

Preparation 3 4-methyltetrahydro-2H-pyran-4-thiol

Step 1: 1,6-Dioxaspiro[2.5]octane: To a suspension oftrimethylsulfoxonium iodide (28.6 g, 130 mmol) in DMSO (200 mL) in atwo-neck RBF (500 mL) was added NaH (5.19 g, 130 mmol, 60% in mineraloil) in portions under N₂ atomsphere at room temperature. Stirring wascontinued for one hour, then a solution of dihydro-2H-pyran-4(3H)-one(10 g, 100 mmol) in DMSO (10 mL) was added dropwise over 5 min. Thereaction mixture was stirred for 1 hr at room temperature, then pouredinto ice-water (300 mL) and extracted with Et₂O (2×200 mL). The organicwas washed with water and brine, dried over MgSO₄, filtered, andconcentrated to give 1,6-dioxaspiro[2.5]octane (4.9 g, 42.9 mmol, 43.0%yield) as colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ: 1.52-1.59 (m,2H) 1.89 (ddd, J=13.20, 8.40, 4.67 Hz, 2H) 2.71 (s, 2H) 3.79-3.95 (m,4H).

Step 2: 6-Oxa-1-thiaspiro[2.5]octane: To a solution of1,6-dioxaspiro[2.5]octane (200 mg, 1.752 mmol) in MeOH (5 mL) was addedthiourea (133 mg, 1.75 mmol), and the reaction mixture was stirred andheated at 80° C. for 4 h. The precipitate that formed during the courseof the reaction was filtered. The filtrate was diluted with Et₂O (100mL), washed with brine, dried over MgSO₄, filtered, and evaporated togive a colorless oil 6-oxa-1-thiaspiro[2.5]octane (216 mg, 1.659 mmol,95% yield). ¹H NMR (CHLOROFORM-d) δ: 3.97 (dt, J=11.3, 4.1 Hz, 2H), 3.76(ddd, J=11.5, 9.2, 2.8 Hz, 2H), 2.49 (s, 2H), 2.22 (ddd, J=13.4, 9.5,3.9 Hz, 2H), 1.55 (d, J=13.4 Hz, 2H).

Step 3: 4-Methyltetrahydro-2H-pyran-4-thiol: To a refluxing solution of6-oxa-1-thiaspiro[2.5]octane (200 mg, 1.54 mmol) in THF (5 mL) was addedLiAlH₄ in THF (0.40 mL, 0.80 mmol) dropwise. The reaction was stirredfor 1 hour, then cooled to 0° C. and quenched with water (1 mL). Themixture was stirred for 10 min and extracted with Et₂O (2×10 mL). Theorganic was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified on silica gel column (10 g) andeluted with 10% EtOAc in hexane to give desired product (94 mg, 46%) asa colorless oil. ¹H NMR (CHLOROFORM-d) δ: 3.78 (dd, J=6.8, 3.3 Hz, 4H),1.73-1.84 (m, 2H), 1.64-1.73 (m, 3H), 1.51 (s, 3H).

Preparation 4

Trans-3-Methyltetrahydro-2H-pyran-4-thiol

Step 1: 3-Methyltetrahydro-4H-pyran-4-one: To a solution of LDA (2.0 Min heptane/THF/ethylbenzene, 12.0 mL, 24.0 mmol) in THF (100 mL) cooledto −78° C. was added a solution of dihydro-2H-pyran-4(3H)-one (2 g, 20.0mmol) and HMPA (3.5 mL, 20.0 mmol) in THF (70 mL) dropwise. Afterstirring for 5 min, MeI (6.25 mL, 100 mmol) in THF (30 mL) was added tothe above solution, the reaction was warmed to 0° C. and kept for 2 h,then warmed to room temperature for 10 min, and then cooled again to 0°C. The reaction mixture was quenched with NH₄Cl (sat'd) and extractedwith Et₂O (2×200 mL). The organic was washed with brine, dried overMgSO₄, filtered, and concentrated. The crude mixture was purified via asilica gel column (100 g), using 10-20% Et₂O in DCM to give an orangeoil 3-methyldihydro-2H-pyran-4(3H)-one (2.2 g, 19.30 mmol, 96% yield).¹H NMR (CHLOROFORM-d) δ: 4.12-4.32 (m, 2H), 3.67-3.81 (m, 2H), 2.60-2.74(m, 1H), 2.54 (dt, J=17.1, 6.1 Hz, 1H), 2.41 (dt, J=14.1, 2.7 Hz, 1H),1.01 (d, J=6.8 Hz, 3H).

Step 2: Trans-3-methyltetrahydro-2H-pyran-4-ol: To a solution of3-methyldihydro-2H-pyran-4(3H)-one (2.28 g, 20.0 mmol) in DCE (50 mL)was added sodium triacetoxyborohydride (8.47 g, 40.0 mmol), followed byacetic acid (3.4 mL, 59.9 mmol) and the reaction mixture was stirred atroom temperature for 16 h. The reaction was quenched with water andextracted with Et₂O (3×20 mL). Organic extracts were combined, washedwith sodium bicarbonate (sat'd) and brine, dried over MgSO₄, filtered,and concentrated. The reaction mixture was purified on a silica gelcolumn (100 g) using 50-60% EtOAc in hexane to give two products (thestructures were confirmed by nOe experiments):

trans-3-methyltetrahydro-2H-pyran-4-ol (206 mg, 9% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ: 0.97 (d, J=13.39 Hz, 3H) 1.63-1.87 (m, 3H) 3.10(d, J=11.37 Hz, 1H) 3.43-3.58 (m, 3H) 3.90-3.99 (m, 1H).

cis-3-methyltetrahydro-2H-pyran-4-ol (790 mg, 34% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ: 0.96 (d, J=6.57 Hz, 3H) 1.58-1.66 (m, 1H) 1.92 (m,J=12.66, 4.64, 2.46, 2.46 Hz, 2H) 2.96-3.07 (m, 1H) 3.35 (td, J=9.85,4.55 Hz, 1H) 3.44 (td, J=11.87, 2.27 Hz, 1H) 3.86 (dd, J=12.25, 3.66 Hz,1H) 3.97-4.03 (m, 1H).

Step 3: cis-3-methyltetrahydro-2H-pyran-4-yl methanesulfonate: To asolution of cis-3-methyltetrahydro-2H-pyran-4-ol (780 mg, 6.71 mmol) inDCM (20 mL) was added methanesulfonyl chloride (0.63 mL, 8.06 mmol)followed by trimethylamine (1.87 mL, 13.43 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 3 h, then quenched with water andextracted with DCM (2×30 mL). The organic was washed with sodiumbicarbonate (sat'd) and brine, dried over MgSO₄, filtered, andconcentrated to give a colorless oilcis-3-methyltetrahydro-2H-pyran-4-yl methanesulfonate (1.4 g, 7.21 mmol,107% yield) which was used for next step without purification.

Step 4: trans-S-3-methyltetrahydro-2H-pyran-4-yl)ethanethioate:Potassium thioacetate (882 mg, 7.72 mmol) was added to a solution ofcis-3-methyltetrahydro-2H-pyran-4-yl methanesulfonate (500 mg, 2.57mmol) in DMA (8 mL) and the reaction was heated at 80° C. for 24 h. Thereaction was cooled to room temperature and extracted with Et₂O (3×30mL). Extracts were combined and washed with water (2×20 mL) and brine,dried over MgSO₄, filtered, and concentrated to give a red oil (singlespot on TLC) as desired producttrans-S-3-methyltetrahydro-2H-pyran-4-yl)ethanethioate (445 mg, 2.55mmol, 99% yield) which was used for next step without purification.

Step 5: trans-3-methyltetrahydro-2H-pyran-4-thiol: Ammonia (2.0 M inMeOH, 10.400 mL, 20.80 mmol) was added totrans-S-3-methyltetrahydro-2H-pyran-4-yl) ethanethioate (440 mg, 2.52mmol) and the reaction mixture was heated at 40° C. for 12 h. Uponcompletion, the mixture was concentrated in vacuo to give an orangesolid. The solid was purified on an ISCO silica gel column (25 g), using10-20% EtOAc in hexane to give desired producttrans-3-methyltetrahydro-2H-pyran-4-thiol (71 mg, 0.54 mmol, 21.27%yield). ¹HNMR (400 MHz, CHLOROFORM-d) δ: 1.02-1.08 (m, 3H) 1.76-1.95 (m,2H) 2.05-2.15 (m, 1H) 3.13 (m, J=9.00, 4.28, 4.28, 2.40 Hz, 1H)3.42-3.58 (m, 2H) 3.64 (dt, J=11.49, 4.48 Hz, 1H) 3.88-3.96 (m, 1H).

Preparation 5 (2R,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-thiol

Step 1: 2,6-Dimethyltetrahydro-2H-pyran-4-ol: To a solution of2,6-dimethyldihydro-2H-pyran-4(3H)-one (3 g, 23.41 mmol) in DCE (60 mL)was added sodium triacetoxyborohydride (14.88 g, 70.2 mmol) followed byacetic acid (8.1 mL, 140 mmol), and the reaction mixture was stirred atroom temperature for 20 h. The reaction was quenched with water andextracted with Et₂O (3×50 mL). The organic was washed with brine, driedover MgSO₄, filtered, and concentrated to give the desired product2,6-dimethyltetrahydro-2H-pyran-4-ol as a colorless oil (3 g, 23.04mmol, 98% yield). ¹H NMR(CHLOROFORM-d) δ: 1.19-1.26 (m, 6H) 1.83 (d,J=12.13 Hz, 2H) 1.93 (dd, J=12.00, 4.67 Hz, 2H) 3.58-3.68 (m, 1H)3.75-3.85 (m, 1H) 3.93 (m, 1H).

Step 2: 2,6-Dimethyltetrahydro-2H-pyran-4-yl methanesulfonate: To asolution of 2,6-dimethyltetrahydro-2H-pyran-4-ol (3 g, 23.04 mmol) inDCM (100 mL) was added mesyl chloride (2.16 mL, 27.7 mmol) and followedby Et₃N (6.42 mL, 46.1 mmol). The reaction mixture was stirred at 0° C.for 1 hr and quenched with water. The reaction mixture was extractedwith DCM (2×50 mL), and the organic was washed with sodium bicarbonate(sat'd) and brine, dried over MgSO₄, filtered, concentrated. The crudemixture was purified on an ISCO silica column (40 g) using 50% EtOAc inhexane to give a white solid 2,6-dimethyltetrahydro-2H-pyran-4-ylmethanesulfonate (2.17 g, 10.42 mmol, 45.2% yield).).

¹H NMR(CHLOROFORM-d) δ: 1.26 (d, J=6.06 Hz, 6H) 1.40-1.51 (m, 2H) 2.12(dd, J=12.13, 4.80 Hz, 3H) 3.03 (s, 3H) 3.42-3.59 (m, 2H) 4.82 (s, 1H).

Step 3: S-(2,6-dimethyltetrahydro-2H-pyran-4-yl)ethanethioate: To asolution of 2,6-dimethyltetrahydro-2H-pyran-4-yl methanesulfonate (2.17g, 10.42 mmol) in DMA (25 mL) was added potassium thioacetate (2.380 g,20.84 mmol) and the reaction mixture was stirred at 65° C. for 20 h. Thereaction mixture was cooled to room temperature, diluted with Et₂O (100mL), and the organic was washed with water (2×20 mL) and brine, driedover MgSO₄, filtered, and concentrated. The crude mixture was purifiedon silica gel (50 g) using 10-20% EtOAc in hexane to give the desiredproduct S-(2,6-dimethyltetrahydro-2H-pyran-4-yl)ethanethioate (1.93 g,10.25 mmol, 98% yield). ¹H NMR (CHLOROFORM-d) δ: 4.03-4.09 (m, 1H), 3.65(dd, J=6.6, 2.3 Hz, 2H), 2.34 (s, 3H), 1.65-1.71 (m, 4H), 1.18 (d, J=6.3Hz, 6H); MS (m/z) 189 (M+H⁺).

Step 4: (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-thiol: Ammonia (2.0Min MeOH, 6.37 mL, 12.75 mmol) was added toS-(2,6-dimethyltetrahydro-2H-pyran-4-yl) ethanethioate (500 mg, 2.66mmol) and the reaction mixture was stirred at 23° C. for 20 h. Thereaction was going slowly and was heated at 40° C. for an additional 4 hfollowed by concentration in vacuo and purification on an ISCO (silicagel column 25 g) using 0-10% EtOAc in hexane to give(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-thiol (308 mg, 79% yield). Thestructure was confirmed by nOe experiment. ¹H NMR (400 MHz,CHLOROFORM-d) δ: 1.20 (d, J=6.32 Hz, 6H) 1.58-1.77 (m, 5H) 3.56-3.68 (m,1H) 3.88-4.04 (m, 2H).

The following intermediate was synthesized in an analogous manner usingp-toluenesulfonyl chloride in step 2 rather than methanesulfonylchloride.

Preparation 6N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylthio)-4-quinolinamine

Method A: A mixture of6-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine(250 mg, 0.60 mmol), tetrahydro-2H-pyran-4-thiol (70 mg, 0.60 mmol),potassium tert-butoxide (200 mg, 1.8 mmol),(oxydi-2,1-phenylene)bis-(diphenylphosphine) (32 mg, 0.060 mmol) andbis(dibenzylidineacetone)palladium (55 mg, 0.06 mmol) in 3.9 mL of DMFwere heated at 100° C. in a sealed, nitrogen-purged vial for 16 h. Thereaction was diluted with EtOAc and water and the layers were separated.The organics were concentrated, and the crude product was purified bycolumn chromatography (Isco CombiFlash, 0% to 10% 2N NH₃/MeOH in DCM) togiveN-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylthio)-4-quinolinamine(80 mg, 35%). MS (m/z) 385 (M+H⁺). 1,4-Dioxane may also be used as thesolvent. In cases where the starting quinoline is an HCl salt, andequivalent of triethylamine may also be added.

Method B: Alternatively, coupling reactions may be performed as follows:To a solution of quinoline (1 eq) in dioxane (0.1 M) was added(oxydibenzene-2,1-diyl)bis(diphenylphosphane) (0.1 eq),tris(dibenzylideneacetone)dipalladium(0) (0.1 eq), potassiumtert-butoxide (1-2 eq), thiol (1.2 eq), and triethylamine (1-3 eq). Theflask was purged with nitrogen, and heated under nitrogen for 3 h at 90°C. before pouring into EtOAc. The organic layer was washed withsaturated sodium bicarbonate. The aqueous layer was washed with 25% EtOHin methylene chloride, then methylene chloride. The organics werecombined, dried over MgSO₄ and concentrated to a brown oil. The residuewas purified via Isco CombiFlash.

The following analogs were made in an analogous manner:

Coupling Structure method

B

B

A

B

B

B

B

B

Preparation 7

Step 1. 2-chloro-5-fluoro-3-pyridinecarboxamide:2-Chloro-5-fluoro-3-pyridinecarboxylic acid (20 g, 110 mmol) wasdissolved in DCM (400 mL), and then DMF (88 ul, 1.1 mmol) was added at0° C. After the DMF addition, oxalyl chloride (26 mL, 300 mmol) wasadded dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 16 hours, and concentrated in vacuo. The resultingyellow liquid was dissolved in 1,4-dioxane (400 mL), cooled to 0° C. andNH₃ (gas) (19.4 g, 1140 mmol) was bubbled through the solution for 30minutes. The mixture was stirred at room temperature for 16 hours. Theresulting white mixture was filtered and the filtrate was concentratedto give the desired product as a white solid (18 g, 89% yield). MS (m/z)175 (M+H⁺); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (d, 1H), 8.10 (s, 1H),8.00 (dd, 1H), 7.88 (s, 1H).

Step 2. 2-chloro-5-fluoro-3-pyridinecarbonitrile:2-Chloro-5-fluoro-3-pyridinecarboxamide (18 g, 102 mmol) was suspendedin DCM (500 mL), and then triethylamine (31 mL, 220 mmol) was added at0° C. Trifluoroacetic anhydride (TFAA) (16 mL, 110 mmol) was addeddropwise to the reaction mixture at 0° C. The white carboxamide startingmaterial disappeared after 20 minutes at 0° C., indicating thecompletion of the reaction. The reaction mixture was stirred at 0° C.for 1 hour. The reaction mixture was diluted with DCM, and then washedwith saturated NaHCO₃(aq). The organic layer was washed with brine,dried over MgSO₄, filtered and the filtrate was concentrated to a brownresidue. The residue was purified by Isco Combiflash (8%-20%EtOAc/Hexane; 330 g column). Collected fractions were combined andconcentrated to give the desired product as a white solid (15 g, 96%yield). MS (m/z) 157 (M+H⁺). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.68 (dd,1H), 8.83 (d, 1H).

Step 3. 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine:2-Chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) was dissolvedin 1-butanol (300 mL), and then hydrazine monohydrate (16.82 mL, 293mmol) was added, followed by hydrochloric acid (4N in dioxane) (0.244mL, 0.977 mmol). The reaction mixture was maintained at 70° C. for 4hours, and the resulting yellow crystalline solid was collected byfiltration (12.5 g, 84% yield). MS (m/z) 153 (M+H⁺). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 5.56 (s, 2H), 7.97 (dd, 1H), 8.39 (m, 1H), 12.07 (s, 1H).

Preparation 8

Step 1: 2-bromo-1-[(1,1-dimethylethyl)thio]-4-nitrobenzene: To a roundbottom flask containing 2-bromo-1-fluoro-4-nitrobenzene (15 g, 68 mmol)and 2-methyl-2-propanethiol (8.4 mL, 75 mmol) in DMF (45 mL) was addedpotassium carbonate (10.37 g, 75 mmol). The reaction was heated to 50°C. for 3 d and partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc (2×) and the combined organics were washed withwater (3×) and brine (1×) and concentrated to dryness to afford2-bromo-1-[(1,1-dimethylethyl)thio]-4-nitrobenzene (19 g, 66 mmol, 98%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (d, J=2.3 Hz, 1H), 8.20(dd, J=8.6, 2.5 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 1.44 (s, 9H)

Step 2: 2-bromo-4-nitrophenyl 1,1-dimethylethyl sulfone: To a roundbottom flask containing 2-bromo-4-nitrophenyl 1,1-dimethylethyl sulfide(15 g, 53 mmol) in MeOH (89 mL) and water (89 mL) was added oxone (49 g,80 mmol). The reaction was stirred at rt for 18 h. An additional amountof oxone (25 g), MeOH (30 mL) and water (30 mL) were added at that time.After 24 h, additional oxone (25 g) was added and the reaction wasstirred at rt for 24 h. The reaction was neutralized with 1N NaOH andDCM was added. The aqueous layer was extracted with DCM (1×) and thecombined organic extracts were washed with brine (1×), dried overmagnesium sulfate and purified via column chromatography in 2 batches(ISCO-Rf, 120 g, 0-30% EtOAc/hexane) to provide 2-bromo-4-nitrophenyl1,1-dimethylethyl sulfone (9.6 g, 30 mmol, 56% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.61 (d, J=2.3 Hz, 1H), 8.43 (dd, J=8.6, 2.3 Hz, 1H),8.27 (d, J=8.8 Hz, 1H), 1.35 (s, 9H)

Step 3: 3-bromo-4-(tert-butylsulfonyl)aniline: A solution of tin (II)chloride dihydrate (17 g, 73 mmol) and conc HCl (24 mL) in MeOH (49 mL)was cooled to 0° C. and 2-bromo-1-(tert-butylsulfonyl)-4-nitrobenzene(4.7 g, 15 mmol) was added in one portion. After 5 h, the reaction wascooled to 0° C. and carefully neutralized with 6N NaOH (˜75 mL). Ethylacetate (350 mL) was added and the mixture was filtered in portions(white precipitate clogs the filter paper). The layers of the filtratewere separated and the aqueous layer was extracted with EtOAc (2×). Thecombined organic extracts were dried over magnesium sulfate andconcentrated to dryness to provide 3-bromo-4-(tert-butylsulfonyl)aniline(3.8 g, 13 mmol, 90% yield). MS (m/z) 236, 238 (M-tbutyl+H⁺). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.57 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H),6.64 (dd, J=8.8, 2.3 Hz, 1H), 6.41 (s, 2H), 1.25 (s, 9H)

The following intermediate was synthesized by an analogous method:

Preparation 9

3-bromo-4-(methylsulfonyl)aniline: To a suspension of2-bromo-1-(methylsulfonyl)-4-nitrobenzene (18.6 g, 66.4 mmol) in aceticacid (221 mL) was added iron (11.13 g, 199 mmol) portionwise at 0° C.The reaction was slowly warmed to room temperature overnight and thenslowly poured into water (150 mL), EtOAc (600 mL), and 2N NaOH (450 mL)with stirring. Solid sodium carbonate (˜300 g) was slowly added to thebrown solution until bubbling ceased and the solution reached pH˜10. Thesolution was transferred to a reparatory funnel, the layers wereseparated and the aqueous layer was extracted with EtOAc (1×). Thecombined organic extracts were concentrated to dryness to yield3-bromo-4-(methylsulfonyl)aniline (10.5 g, 42.0 mmol, 63.2% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.66 (d, J=8.6 Hz, 1H), 6.94 (d, J=2.0 Hz,1H), 6.62 (dd, J=8.7, 2.1 Hz, 1H), 6.36 (s, 2H), 3.19 (s, 3H). MS (m/z)250, 252 (M+H)

Preparation 10

Step 1: Diethyl{[(3-chloro-4-iodophenyl)amino]methylidene}propanedioate:3-chloro-4-iodoaniline (15 g, 59 mmol) was dissolved in diethyl[(ethyloxy)methylidene]propanedioate (19 mL, 95 mmol) and heated to 160°C. for 4 hours under a reflux condenser. The condenser was then removedto allow EtOH to boil off. After an hour, it was cooled to rt where itsolidified, was broken up, and the solid suspended in hexanes. Themixture was filtered and the cake was washed several times with hexanesto afford a gray solid (23 g, 91%). MS (m/z) 424.0 (M+H)⁺.

Step 2: Ethyl 7-chloro-4-hydroxy-6-iodo-3-quinolinecarboxylate: Todiphenyl ether (100 mL, 630 mmol) at 240° C. was added diethyl{[(3-chloro-4-iodophenyl)amino]methylidene}propanedioate (18 g, 43 mmol)in portions. The reaction was heated for 5 hours before it was cooled tort. After reaching rt, the reaction was diluted with hexanes (150 mL)and the suspension was filtered. The cake was rinsed with hexanes (2×100mL) and then dried under vacuum (6.7 g, 41%).

Step 3: 7-Chloro-4-hydroxy-6-iodo-3-quinolinecarboxylic acid: Ethyl7-chloro-4-hydroxy-6-iodo-3-quinolinecarboxylate (6.7 g, 18 mmol) andNaOH (3.5 g, 89 mmol) were suspended in THF (50 mL) and water (50 mL).The reaction was then heated to 70° C. overnight. The mixture was cooledto rt where it was partially concentrated to remove THF. The aqueoussolution was then acidified using conc HCl. The resulting suspension wasfiltered and the cake was washed with water (2×100 mL) and then driedunder vacuum overnight to afford the desired product (6.4 g, 93%). ¹HNMR (DMSO-d₆) δ 14.78 (s, 1H), 13.47 (s, 1H), 8.97 (s, 1H), 8.70 (s,1H), 7.99 (s, 1H).

Step 4: 7-Chloro-6-iodo-4-quinolinol: To diphenyl ether (44 mL, 276mmol) at 240° C. was added7-chloro-4-hydroxy-6-iodo-3-quinolinecarboxylic acid (6.4 g, 18 mmol)portion-wise. The mixture was heated for 3 hours before it was cooled tort overnight. The reaction was diluted with hexanes (200 mL) andsonicated. The suspension was filtered and the cake was washed withhexanes (2×100 mL) and dried under vacuum to afford the desired product(4.9 g, 71%). MS (m/z) 306.0 (M+H)⁺.

Step 5: 4,7-Dichloro-6-iodoquinoline: 7-chloro-6-iodo-4-quinolinol (4.9g, 16 mmol) was suspended in POCl₃ (50 mL, 536 mmol) and stirred at rtfor 72 hours. The mixture was then concentrated and the residue wascooled to 0° C. and carefully quenched by the addition of sat aq Na₂CO₃.The resulting suspension was filtered and the cake was rinsed with water(2×50 mL). After drying the material under vacuum it was dissolved inDCM and concentrated onto silica gel. The dry load was purified by flashchromatography (20->50% EtOAc in hexanes). Concentration of fractionsafforded the desired product as a white solid (3.4 g, 63%). ¹H NMR(DMSO-d₆) δ 8.90 (d, J=4.8 Hz, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 7.84 (d,J=4.8 Hz, 1H); MS (m/z) 323.9 (M+H)⁺.

Preparation 11 Ethyl 3-amino-4-methyl-1H-pyrazole-5-carboxylate

To a stirred solution of propiononitrile (1 g, 18.16 mmol) in THF (40mL) cooled to −78° C. was added LDA in heptane/THF/ethylbenzene (10.89mL, 21.79 mmol) dropwise. The reaction mixture was stirred for 1 hr,then added to a solution of diethyl oxalate (2.65 g, 18.16 mmol) in THF(40 mL) cooled to −78° C. The resulting solution was stirred at −78° C.for 2 h, allowed warm to 0° C. and then quenched by addition of aqueousNH₄Cl. 3N HCl was then added to achieve pH=5. The two layers wereseparated and the aqueous layer was extracted with EtOAc (2×100 mL). Theextracts were combined, washed with brine, dried over MgSO₄, filtered,and concentrated. A yellow precipitate was formed upon partialconcentration and was filtered. The remaining solvent was removed togive a brown oil. The residue oil and hydrazine (1.140 mL, 36.3 mmol)were dissolved in acetic acid (3 mL) and benzene (100 mL), and wererefluxed for 16 h using Dean Stark trap. 1.5 mL of water was collected.The reaction was cooled to room temperature, and the solution wasdecanted away from precipitate on the bottom of the flask. The solventwas removed in vacuo, and brine (20 mL) was added and then extractedwith EtOAc (3×70 mL). The combined extracts were washed with water,dried over MgSO₄, filtered, and concentrated to give a colorless oil.The precipitate from the reaction was partitioned between EtOAc andsaturated sodium bicarbonate and the layers were separated. The organiclayer was washed with brine, dried over MgSO₄, filtered, and combinedwith the oil above, and the solvent was removed in vacuo to give a whitesolid ethyl 3-amino-4-methyl-1H-pyrazole-5-carboxylate (1.92 g, 11.35mmol, 62.5% yield) as the desired product). ¹H NMR (Chloroform-d) δ:4.37 (q, J=7.1 Hz, 2H), 2.15 (s, 3H), 1.38 (t, J=7.2 Hz, 3H); MS (m/z)170 (M+H⁺).

Example 16-(tert-Butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine

Step 1. 6-(tert-butylthio)-4-chloro-7-methoxyquinoline: A mixture of6-bromo-4-chloro-7-methoxyquinoline (50 g, 183 mmol), Pd(Ph₃P)₄ (5.30 g,4.59 mmol), sodium carbonate (48.6 g, 459 mmol) and 1,4-dioxane (895 mL)was purged with nitrogen for 10 minutes. 2-methyl-2-propanethiol (tBuSH;22.75 mL, 202 mmol) was added and the reaction was heated at 70° C. for4 d. The reaction was cooled to rt and flushed through a silica gel plugthat had been pre-wetted with EtOAc using 100% EtOAc as the eluent. Theproduct-containing fractions were triturated with MeOH and combined toafford 6-(tert-butylthio)-4-chloro-7-methoxyquinoline (37.5 g, 128 mmol,69.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.79 (d, J=4.8 Hz, 1H),8.25 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.54 (s, 1H), 3.99 (s, 3H), 1.31(s, 9H). MS (m/z) 282.

Step 2. 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline: To asolution of 6-(tert-butylthio)-4-chloro-7-methoxyquinoline (18.5 g, 63.0mmol) in EtOAc (315 mL) and water (315 mL) was added oxone (44.6 g, 72.5mmol). The reaction was stirred at rt for 18 h. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×). Thecombined organic extracts were concentrated to dryness, dissolved in aminimal amount of 10% MeOH/DCM, loaded onto a Biotage 340 g silicacolumn and purified via column chromatography (Biotage SP-1, 340 g, 100%EtOAc for 20 min, then 0%-20% MeOH/EtOAc). The cleanest fractions wereconcentrated to dryness and triturated with EtOAc to provide6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (15.2 g). ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.95 (d, J=4.8 Hz, 1H), 8.65 (s, 1H), 7.71-7.79 (m,2H), 4.04 (s, 3H), 1.31 (s, 9H). MS (m/z) 314.

Step 3.6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine:To a solution of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (4.7g, 14.98 mmol) and 4,5-dimethyl-1H-pyrazol-3-amine (1.998 g, 17.97 mmol)in EtOH (74.9 mL) was added conc. HCl (2 drops). The reaction was heatedat 70° C. for 42 h. The reaction was concentrated to dryness andpartitioned between DCM and sat. sodium bicarbonate. The aqueous layerwas extracted with DCM (1×) and the combined organic extracts werewashed with brine (1×) and concentrated to dryness. The material wastriturated with 1:1 acetonitrile/water (60 mL) (2×) and dried in avacuum oven overnight to afford6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine(4.3 g, 11.07 mmol, 73.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.26(s, 1H), 9.32 (s, 1H), 8.94 (s, 1H), 8.40 (d, J=5.3 Hz, 1H), 7.40 (s,1H), 6.41 (d, J=5.3 Hz, 1H), 3.96 (s, 3H), 2.20 (s, 3H), 1.78 (s, 3H),1.24-1.38 (m, 9H). MS (m/z) 389.

Example 2N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfinyl)-4-quinolinamine

To a solution of iron(III)chloride (1 mg, 6 umol) andN-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylthio)-4-quinolinamine(80 mg, 0.21 mmol) in acetonitrile (1 mL) stirred for 5 minutes wasadded periodic acid (52 mg, 0.23 mmol). After 4 hours, the reaction wasquenched with saturated aqueous Na₂S₂O₃ and extracted with DCM. Theorganic layer was concentrated and purified by silica gel chromatography(0% to 10% 2N NH₃/MeOH in DCM). Purified material contained some overoxidized sulfone and was repurified by reverse phase HPLC to giveN-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfinyl)-4-quinolinamine(10 mg, 12%). ¹H NMR (DMSO-d₆) δ ppm 12.29 (br. s., 1H), 9.43-9.62 (br.s., 1H), 8.99 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.44 (s, 1H), 6.49 (s,1H), 4.05 (s, 3H), 3.93 (d, J=11.2 Hz, 2H), 3.81 (d, J=7.3 Hz, 1H),3.20-3.41 (m, 2H), 2.20 (s, 3H), 1.80 (s, 3H), 1.63-1.73 (m, 4H). MS(m/z) 401 (M+H⁺).

Example 36-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine

Step 1: 4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline:6-bromo-4-chloro-7-(methyloxy)quinoline (700 mg, 2.6 mmol), sodiumcarbonate (1.1 g, 6.4 mmol), 1,4-dioxane (25.5 mL),tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol), andt-butylthiol (0.29 mL, 2.6 mmol) were added to microwave vial and purgedwith nitrogen for 10 min. After heating at 80° C. overnight, thereaction was only ˜50% complete and additionaltetrakis(triphenylphosphine)palladium(0) (150 mg) was added. Thereaction was purged with nitrogen for 10 min, thiol (290 uL) was addedand the reaction heated at 100° C. overnight. The reaction waspartitioned between EtOAc and a solution of aqueous sodiumthiosulfate/sodium bicarbonate (5:1, 2M). The aqueous layer wasextracted with EtOAc (1×) and the combined organic extracts weredry-loaded onto silica. The crude product was purified via columnchromatography (ISCO-Rf (0-100% EtOAc/hexane)) to afford4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline (260 mg,0.91 mmol, 36% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.79 (d, J=4.8Hz, 1H), 8.26 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.55 (s, 1H), 3.99 (s,3H), 1.32 (s, 9H). MS (m/z) 282 (M+H)

Step 2:6-[(1,1-dimethylethyl)thio]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine:A mixture of 4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline(250 mg, 0.89 mmol), 4,5-dimethyl-1H-pyrazol-3-amine (99 mg, 0.89 mmol)and EtOH (8.9 mL) was treated with 2 drops of concentrated HCl andheated at 80° C. for 1 h. The reaction was concentrated to dryness,suspended in DCM and filtered to provide6-[(1,1-dimethylethyl)thio]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine(175 mg, 0.45 mmol, 50% yield) as the HCl salt. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 14.05 (d, J=1.5 Hz, 1H), 12.67 (s, 1H), 10.68 (s, 1H),8.92 (s, 1H), 8.44 (d, J=6.8 Hz, 1H), 7.42 (s, 1H), 6.66 (d, J=7.1 Hz,1H), 4.00 (s, 3H), 2.24 (s, 3H), 1.84 (s, 3H), 1.30 (s, 9H). MS (m/z)357 (M+H)

Step 3:6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine:A mixture of6-[(1,1-dimethylethyl)thio]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine(184 mg, 0.52 mmol), THF (4.9 mL), water (246 μl) and oxone (159 mg,0.258 mmol) was stirred at rt for 2 h. The reaction was partitionedbetween EtOAc and saturated sodium bicarbonate. The aqueous layer wasextracted with EtOAc (1×) and the combined organics were dry-loaded ontosilica gel and purified via column chromatography (ISCO-Rf, 12 g, 0-20%MeOH/DCM) which provided 96 mg of desired product and 65 mg of 1:1SM/Pdt. The 65 mg of 1:1 SM/Pdt was treated with THF (2 mL), water (0.2mL) and oxone (30 mg). The reaction was stirred for 1 h. Again, thereaction was partitioned between EtOAc and saturated sodium bicarbonate.The aqueous layer was extracted with EtOAc (1×) and the combinedorganics were combined with the 96 mg of 92% pure material, dry-loadedonto silica gel and purified via column chromatography (ISCO-Rf, 4 g,0-20% MeOH/DCM) to provide6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine(90 mg, 0.24 mmol, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.21 (s,1H), 9.13 (s, 1H), 8.66 (s, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.32 (s, 1H),6.40 (d, J=5.3 Hz, 1H), 3.86-3.98 (m, 3H), 2.20 (s, 3H), 1.78 (s, 3H),1.17 (s, 9H). MS (m/z) 373 (M+H)

The sulfone can be generated in step three by adding a full equivalentof oxone. The following examples were made in an analogous mannerbeginning with the appropriate quinoline from the Preparations aboveand/or commercial sources:

MS Ex. Structure Name (M + H)⁺ NMR 4

2-((4-((4,5- dimethyl-1H- pyrazol-3- yl)amino)-7- methoxyquinolin-6-yl)sulfonyl)-2- methylpropan-1- ol 405 ¹H NMR (400 MHz, DMSO-d6)Shift: 12.27 (s, 1 H), 9.30 (s, 1 H), 8.91 (s, 1 H), 8.40 (d, J = 5.3Hz, 1 H), 7.39 (s, 1 H), 6.40 (d, J = 5.3 Hz, 1 H), 4.88 (t, J = 6.1 Hz,1 H), 3.96 (s, 3 H), 3.59 (d, J = 6.1 Hz, 2 H), 2.20 (s, 3 H), 1.79 (s,3 H), 1.28 (s, 6 H)

Example 5N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine

N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylthio)-4-quinolinamine(150 mg, 0.39 mmol) and oxone (240 mg, 0.39 mmol) were taken up in THF(1 mL) and water (1 mL) and stirred at room temperature. Once completeby LCMS, the reaction was concentrated, dissolved in MeOH, and purifiedby reverse phase HPLC. Desired fractions were neutralized using aMP-carbonate resin which was filtered off and rinsed with MeOH. Thefiltrate was concentrated and the residue was dissolved in 2 mL of waterand MeCN each. The solution was sonicated and the resulting suspensionwas filtered and dried under vacuum to provide the title compound (29mg, 17%). ¹H NMR (DMSO-d₆) δ 12.25 (br. s., 1H), 9.29 (br. s., 1H), 8.96(s, 1H), 8.41 (d, J=5.3 Hz, 1H), 7.44 (s, 1H), 6.46 (d, J=4.8 Hz, 1H),4.04 (s, 3H), 3.88-3.98 (m, 2H), 3.74-3.88 (m, 1H), 3.32-3.41 (m, 2H),2.20 (s, 3H), 1.80 (s, 3H), 1.69 (m, 4H); MS (m/z) 417 (M+H⁺).

Alternatively, EtOAc or MeOH may be used as the organic component in thesolvent mixture in ratios varying from 4:1 to 1:1 organic:aqueous.

The following examples were made in an analogous manner beginning withthe appropriate quinoline from the Preparations above or commercialsources:

MS Ex. Structure Name (M + H)⁺ NMR  6

2-((4-((4,5-dimethyl-1H- pyrazol-3-yl)amino)-7- methylquinolin-6-yl)sulfonyl)ethanol 361 ¹H NMR (DMSO-d6) Shift: 12.36 (br. s., 1H), 9.62(br. s., 1H), 9.07 (s, 1H), 8.47 (d, J = 5.8 Hz, 1H), 7.83 (s, 1H), 6.56(d, J = 5.3 Hz, 1H), 4.86 (br. s., 1H), 3.77 (m, 2H), 3.58 (t, J = 6.1Hz, 2H), 2.77 (s, 3H), 2.21 (s, 3H), 1.81 (s, 3H)  7

N-(4,5-dimethyl-1H-pyrazol-3- yl)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)-7- methoxyquinolin-4-amine 445 ¹H NMR (400 MHz,METHANOL-d4) Shift: 8.95 (s, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.44 (s,1H), 6.49 (br. s., 1H), 4.13 (s, 3H), 4.02-4.09 (m, 1H), 3.67-3.88 (m,2H), 2.30 (s, 3H), 1.90 (s, 3H), 1.78-1.86 (m, 2H), 1.64-1.72 (m, 2H),1.24 (s, 6H)  8

N-(4,5-Dimethyl-1H-pyrazol-3- yl)-7-methoxy-6-((4-methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin-4-amine 431 ¹H NMR(400 MHz, DMSO-d₆) δ 1.41 (s, 3H) 1.42-1.50 (m, 2H) 1.79 (s, 3H)2.09-2.19 (m, 2H) 2.20 (s, 3H) 3.41-3.52 (m, 2H) 3.80-3.89 (m, 2H) 3.96(s, 3H) 6.37-6.46 (m, 1H) 7.41 (s, 1H) 8.37-8.47 (m, 1H), 8.93 (s, 1H)9.37 (br. s., 1H) 12.28 (br. s, 1H)  9

N-(4,5-Dimethyl-1H-pyrazol-3- yl)-7-methoxy-6-((2-methoxyethyl)sulfonyl)quinolin- 4-amine 391 ¹H NMR (400 MHz, DMSO-d₆) δ1.80 (s, 3H) 2.20 (s, 3H) 3.09 (s, 3H) 3.67 (t, J = 5.31 Hz, 2H) 3.74(t, J = 5.56 Hz, 2H), 4.05 (s, 3H), 6.47 (d, J = 5.31 Hz, 1H) 7.42 (s,1H) 8.40 (d, J = 5.56 Hz, 1H) 8.96 (s, 1H) 9.26 (br. s., 1H) 12.25 (br.s., 1H) 10

N-(4,5-Dimethyl-1H-pyrazol-3- yl)-7-methoxy-6-(((3R,4R)-3-methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin-4-amine 431 ¹H NMR(400 MHz, METHANOL-d₄) δ 1.25 (d, J = 7.33 Hz, 3H) 1.59-1.68 (m, 1H)1.89 (s, 3H) 2.15-2.26 (m, 2H) 2.29 (s, 3H) 3.03 (s, 3H) 3.38-3.47 (m,1H) 3.55-3.62 (m, 1H) 3.72-3.80 (m, 1H) 3.97-4.08 (m, 2H) 6.48 (d, J =5.81 Hz, 1H) 7.44 (s, 1H) 8.39 (d, 5.81 Hz, 1H) 8.96 (s, 1H) 11

N-(4,5-dimethyl-1H-pyrazol-3- yl)-6-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4- yl)sulfonyl)-7-methoxyquinolin- 4-amine445 ¹H NMR (500 MHz, DMSO-d₆) δ 1.05 (d, J = 6.23 Hz, 6H) 1.50-1.63 (m,2H) 1.78 (s, 3H) 1.98 (d, J = 14.62 Hz, 2H) 2.19 (s, 3H) 3.89-3.95 (m,1H) 3.96-4.06 (m, 5H) 6.42 (br. s., 1H) 7.43 (s, 1H) 8.41 (br. s., 1H)8.99 (s, 1H) 9.33 (br. s., 1H) 12.26 (br. s., 1H)

Example 126-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-ol

A solution of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine(170 mg, 0.44 mmol) and sodium propane-2-thiolate (260 mg, 2.6 mmol) washeated at 150° C. in DMF for 3 h. The residue was purified by reversephase chromatography (6% to 75% 0.1% TFA in MeCN in 0.1% TFA in water;Sum 30×150 mm Waters Sunfire column). The fractions were collected andconcentrated to an oil. The crude mixture was purified with preparatoryTLC (elution with 10% NH₄OH in iPrOH). The desired spot was scraped off,the product dissolved in MeOH, filtered and the product was isolated asa yellow solid6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-ol(23 mg, 14% yield) by evaporation of the solvent. ¹H NMR (400 MHz,methanol-d₄) δ=8.86 (s, 1H), 8.04 (d, J=6.6 Hz, 1H), 6.96 (s, 1H), 6.27(d, J=6.6 Hz, 1H), 2.30 (s, 3H), 1.44 (s, 9H), 1.93 (s, 3H). MS (m/z)375 (M+H⁺).

Example 13 6-(tert-butylsulfonyl)-N-(5-fluoro-1H-pyrazolo[3,4-1)]pyridin-3-yl)-7-methoxyquinolin-4-amine

Step 1: 4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline:

Method A: 6-bromo-4-chloro-7-(methyloxy)quinoline (1.87 g, 5.42 mmol),sodium carbonate (1.44 g, 13.55 mmol), and Pd(PPh₃)₄ (0.31 g, 0.27 mmol)in DMF (30 mL) were deoxygenated for 10 minutes in a sealed tube.2-methyl-2-propanethiol (0.62 mL, 5.42 mmol) was added. The mixture washeated to 60° C. overnight. The reaction mixture was partitioned betweenEtOAc and a saturated solution of sodium thiosulfate and sodiumbicarbonate (v/v 5:1). The aqueous layer was extracted with EtOAc twiceand the combined EtOAc layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (0-35% EtOAc/Hexane) to yield the title compound (1.51 g,85%). MS (m/z) 282 (M+H)⁺. Alternatively, this reaction can be run usingNaHCO₃ as the base or using 1,4-dioxane as the solvent. Reactiontemperatures vary from 50° C. to 100° C. based on the substrate.

Method B: Alternatively, coupling reactions may be performed as follows:To a solution of quinoline (1 eq) in dioxane (0.1 M) was added(oxydibenzene-2,1-diyl)bis(diphenylphosphane) (0.1 eq),tris(dibenzylideneacetone)dipalladium(0) (0.1 eq), potassiumtert-butoxide (1.25 eq), thiol (1.2 eq), and triethylamine (3 eq). Theflask was purged with nitrogen, and heated under nitrogen for 3 h at 90°C. before pouring into EtOAc. The organic layer was washed withsaturated sodium bicarbonate. The aqueous layer was washed with 25% EtOHin methylene chloride, then methylene chloride. The organics werecombined, dried over MgSO₄ and concentrated to a brown oil. The residuewas purified via Isco CombiFlash.

Step 2: 4-chloro-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)quinoline:4-Chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline (1.03 g,3.66 mmol) and oxone (3.37 g, 5.48 mmol) in MeOH (10 mL) and water (10mL) were stirred at rt. Once the reaction was complete it was filtered,and the cake was washed with MeOH. The filtrate was concentrated,dissolved in EtOAc, dried over sodium sulfate, then filtered andconcentrated. The residue was purified via flash chromatography (0-50%EtOAc/Hexane) to yield the title compound (0.46 g, 39% yield). MS (m/z)314 (M+H)⁺. Alternatively this reaction can be done using a THF:Water orEtOAc:Water solvent system (4:1, 2:1, or 1:1).

Step 3:6-(tert-butylsulfonyl)-N-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-methoxyquinolin-4-amine:4-Chloro-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)quinoline (200 mg,0.64 mmol), 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (97 mg, 0.64mmol), and EtOH (1.5 mL) were combined along with 2 drops ofconcentrated HCl and heated to 80° C. overnight. The mixture was dilutedwith MeOH:Et₂O and filtered. The cake was rinsed with Et₂O. Thecollected solid was then dissolved in MeOH and free based usingMP-carbonate resin. The resin was filtered off and rinsed with MeOH. Thefiltrate was concentrated to afford the desired product as a yellowsolid (93 mg, 32%). ¹H NMR (DMSO-d₆) δ 13.54 (br. s., 1H), 10.01 (s,1H), 9.05 (s, 1H), 8.62 (br. s., 1H), 8.57 (d, J=5.3 Hz, 1H), 8.17 (d,J=8.8 Hz, 1H), 7.50 (s, 1H), 7.28 (d, J=5.3 Hz, 1H), 3.99 (s, 3H), 1.33(s, 9H); MS (m/z) 430 (M+H)⁺.

Alternatively this reaction can be done using NMP or isopropyl alcoholas the solvent and/or by heating to 150° C. in a microwave reactor. Whenusing NMP as solvent, the reaction mixture is injected directly onto areverse phase HPLC for purification.

The following examples were made in an analogous manner beginning withthe appropriate quinoline from the above preparations and/or commercialsources: MS Step 1 Ex Structure Name (M + H)⁺ NMR Method  14

N-[4-chloro-3- (methyloxy)phenyl]-6- [(1,1- dimethylethyl)sulfonyl]-7-(methyloxy)-4- quinolinamine 455 ¹H NMR (400 MHz, DMSO-d) δ ppm 1.31 (s,9H), 3.86 (s, 3H), 3.97 (s, 3H), 6.95 (d, J = 5.3 Hz, 1H), 6.97 (dd, J =8.7 Hz, 1.9 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H),7.46 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.88 (s, 1H), 9.54 (s, 1H). A 15

N-(7-Chloro-1H-indazol-3- yl)-7-methoxy-6-((4- methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin-4- amine 487 ¹H NMR (400 MHz, DMSO-d₆) δ1.42 (s, 3H) 1.49 (s, 2H) 2.09-2.23 (m, 2H) 3.47 (s, 2H) 3.79-3.89 (m,2H) 3.99 (s, 3H) 7.07-7.20 (m, 2H) 7.47-7.57 (m, 2H) 7.76 (d, J = 8.08Hz, 1H) 8.55 (d, J = 5.05 Hz, 1H) 9.07 (s, 1H) 10.05 (s, 1H) 13.36 (br.s., 1H) B  16

N-[4-chloro-3- (methyloxy)phenyl]-7- (methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4- quinolinamine 463 ¹H NMR (400 MHz, DMSO-d6) δppm 9.56 (s, 1H), 8.89 (s, 1H), 8.53 (d, J = 5.3 Hz, 1H), 7.50 (s, 1H),7.43 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.95-7.02 (m, 2H),4.06 (s, 3H), 3.93 (d, J = 10.9 Hz, 2H), 3.86 (s, 4H), 3.36 (br. s.,2H), 1.69 (d, 4H) A  17

N-1,3-benzothiazol-5-yl-7- (methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4- quinolinamine 456 ¹H NMR (400 MHz, DMSO-d6) δppm 9.72 (s, 1H), 9.44 (s, 1H), 8.95 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H),8.21 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.49-7.57 (m, 2H),6.94 (d, J = 5.3 Hz, 1H), 4.07 (s, 3H), 3.94 (d, J = 7.6 Hz, 2H),3.80-3.89 (m, 1H), 3.35-3.41 (m, 2H), 1.67-1.73 (m, 4H) A  18

2-{[4-{[4-chloro-3- (methyloxy)phenyl]amino}- 7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol 423 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s,1H), 8.87 (s, 1H), 8.53 (d, J = 5.3 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J =8.3 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.95-7.03 (m, 2H), 4.83 (t, J =5.3 Hz, 1H), 4.06 (s, 3H), 3.86 (s, 3H), 3.62-3.75 (m, 4H) A  19

N-(5-fluoro-1H-indazol-3- yl)-7-(methyloxy)-6- (tetrahydro-2H-pyran-4-ylsulfonyl)-4- quinolinamine 457 ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.91(s, 1H), 9.87 (s, 1H), 9.08 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 7.54-7.65(m, 2H), 7.52 (s, 1H), 7.31 (td, 1H), 7.21 (d, J = 5.3 Hz, 1H), 4.07 (s,3H), 3.94 (d, J = 11.1 Hz, 2H), 3.80-3.89 (m, 1H), 3.37 (d, J = 5.3 Hz,2H), 1.65-1.75 (m, 4H) A  20

2-{[4-[(4,5-dimethyl-1H- pyrazol-3-yl)amino]-7- (methyloxy)-6-quinolinyl]sulfonyl}ethanol 377 ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.23(s, 1H), 9.24 (s, 1H), 8.95 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 7.42 (s,1H), 6.47 (d, J = 5.3 Hz, 1H), 4.83 (t, J = 5.4 Hz, 1H), 4.04 (s, 3H),3.59-3.77 (m, 4H), 2.20 (s, 3H), 1.80 (s, 3H) A  21

N-[4-chloro-3- (methyloxy)phenyl]-6-[(1- methylethyl)sulfonyl]-7-(methyloxy)-4- quinolinamine 421 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.55(s, 1H), 8.89 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.50 (s, 1H), 7.43 (d,J = 8.6 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.94-7.03 (m, 2H), 4.05 (s,3H), 3.86 (s, 3H), 3.74-3.83 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H) A  22

N-1,3-benzothiazol-5-yl-6- [(1-methylethyl)sulfonyl]- 7-(methyloxy)-4-quinolinamine 414 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.43 (s,1H), 8.96 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H),8.04 (d, J = 2.0 Hz, 1H), 7.46-7.61 (m, 2H), 6.94 (d, J = 5.3 Hz, 1H),4.06 (s, 3H), 3.71-3.89 (m, 1H), 1.23 (d, 6H) A  23

N-(4,5-dimethyl-1H- pyrazol-3-yl)-6-[(1- methylethyl)sulfonyl]-7-(methyloxy)-4- quinolinamine 375 ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.23(s, 1H), 9.26 (s, 1H), 8.96 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 7.43 (s,1H), 6.47 (d, J = 5.6 Hz, 1H), 4.03 (s, 3H), 3.72-3.82 (m, 1H), 2.20 (s,3H), 1.80 (s, 3H), 1.22 (d, J = 6.8 Hz, 6H) A  24

N-(5-fluoro-1H-indazol-3- yl)-6-[(1- methylethyl)sulfonyl]-7-(methyloxy)-4- quinolinamine 415 ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.90(s, 1H), 9.87 (s, 1H), 9.09 (s, 1H), 8.54 (d, J = 5.6 Hz, 1H), 7.55-7.63(m, 2H), 7.52 (s, 1H), 7.28-7.36 (m, 1H), 7.22 (d, J = 5.6 Hz, 1H), 4.06(s, 3H), 3.76-3.85 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H) A  25

2-{[4-(1,3-benzothiazol-5- ylamino)-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol 416 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.70(br. s., 1H), 9.43 (s, 1H), 8.94 (s, 1H), 8.50 (br. s., 1H), 8.19 (br.s., 1H), 8.03 (br. s., 1H), 7.48 (br. s., 2H), 6.94 (br. s., 1H), 4.86(br. s., 1H), 4.06 (s, 3H), 3.61-3.78 (m, 4H) A  26

6-(isopropyl-sulfonyl)-7- methoxy-N-(4-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)quinolin-4- amine 429 ¹H NMR (400 MHz, DMSO-d₆) δ 13.65(br. s., 1H), 9.41-9.80 (m, 1H), 8.85-9.10 (m, 1H), 8.34-8.61 (m, 1H),7.37-7.68 (m, 1H), 6.24 (br. s., 1H), 4.05 (s, 3H), 3.81 (m, 1H),1.87-2.05 (m, 3H), 1.22 (d, J = 6.82 Hz, 6H) A  27

6-(tert-butylsulfonyl)-7- methoxy-N-(4-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)quinolin-4- amine 443 ¹H NMR (400 MHz, DMSO-d₆) δ 13.97(br. s., 1H), 9.00-9.24 (m, 1H), 8.37-8.62 (m, 1H), 7.51-7.65 (m, 1H),6.42 (br. s., 1H), 4.03 (s, 3H), 1.99 (s, 3H), 1.34 (s, 9H) A  28

6-(tert-butylsulfonyl)-N- (4,5-dimethyl-1H-pyrazol-3-yl)-7-ethoxyquinolin-4- amine 403 ¹H NMR (CDCl₃) δ 11.53 (br. s., 1H),10.71 (br. s., 1H), 9.06 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 8.15 (s,1H), 6.50 (d, J = 6.8 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H),1.83 (s, 3H), 1.57 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H) B  29

6-(tert-butylsulfonyl)-7- ethoxy-N-(5-fluoro-1H-indazol-3-yl)quinolin-4- amine 443 ¹H NMR (400 MHz, methanol-d₄) δ 9.03(s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 7.58 (td, J = 9.1, 2.4 Hz, 1H), 7.46(s, 1H), 7.38 (dd, J = 9.1, 2.4 Hz, 1H), 7.29 (td, J = 9.1, 2.4 Hz, 1H),6.98 (d, J = 5.7 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 1.58 (t, J = 7.0 Hz,3H), 1.46 (s, 9H) B  30

7-chloro-N-(4,5-dimethyl- 1H-pyrazol-3-yl)-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 421 ¹H NMR (DMSO-d₆) 12.32 (br s, 1H),9.56 (s, 1H), 9.16 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.08 (s, 1H), 6.62(d, J = 4.0 Hz, 1H), 3.81-4.01 (m, 2H), 3.71-3.83 (m, 1H), 3.35-3.42 (m,2H), 2.21 (s, 3H), 1.80 (s, 3H), 1.65-1.78 (m, 4H). A  31

N-(4,5-dimethyl-1H- pyrazol-3-yl)-7-methyl-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 401 ¹H NMR (DMSO-d₆) 12.52 (br s, 1H),9.15 (s, 1H), 8.52 (d, J = 6.3 Hz, 1H), 7.89 (s, 1H), 6.68 (d, J = 6.3Hz, 1H), 3.93 (m, 2H), 3.63-3.77 (m, 1H), 3.26-3.43 (m, 2H), 2.82 (s,3H), 2.23 (s, 3H), 1.83 (s, 3H), 1.65-1.78 (m, 4H). A  32

7-chloro-N-(5-fluoro-1H- indazol-3-yl)-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 461 ¹H NMR (DMSO-d₆) 9.28 (s, 1H), 8.56(s, 1H), 8.03-8.14 (m, 1H), 7.50-7.61 (m, 2H), 7.26-7.36 (m, 2H),3.87-4.00 (m, 3H), 3.35-3.43 (m, 2H), 1.70-1.81 (m, 4H). A  33

N-(5-fluoro-1H-indazol-3- yl)-7-methyl-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 441 ¹H NMR (DMSO-d₆) 13.03 (s, 1H), 9.15(s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 7.92 (s, 1H), 7.60 (dd, J = 9.0, 4.3Hz, 1H), 7.56 (dd, J = 9.0, 1.8 Hz, 1H), 7.33 (td, J = 9.0, 2.3 Hz, 1H),7.23 (d, J = 5.8 Hz, 1H), 3.93 (m, 2H), 3.69 (tt, J = 10.2, 5.2 Hz, 1H),3.29-3.43 (m, 2H), 2.81 (s, 3H), 1.63-1.82 (m, 4H). A  34

N-(5-fluoro-1H-indazol-3- yl)-6-((tetrahydro-2H- pyran-4-yl)sulfonyl)-7-(trifluoromethyl)quinolin-4- amine 495 ¹H NMR (DMSO-d₆) 9.33 (s, 1H),7.47-7.58 (m, 2H), 7.38-7.45 (m, 4H), 7.31-7.36 (m, 1H), 7.20-7.29 (m,1H), 3.88-3.99 (m, 2H), 3.51-3.64 (m, 1H), 3.26-3.32 (m, 2H), 1.69-1.84(m, 4H). A  35

6-(tert-butylsulfonyl)-N-(5- fluoro-1H-indazol-3-yl)-7-(trifluoromethyl)quinolin-4- amine 467 ¹H NMR (DMSO-d₆) 13.43 (s, 1H),9.50 (s, 1H), 8.78 (d, J = 6.3 Hz, 1H), 8.58 (s, 1H), 7.69 (dd, J = 9.2,4.1 Hz, 1H), 7.51 (dd, J = 8.9, 1.9 Hz, 1H), 7.39 (td, J = 9.1, 2.4 Hz,1H), 7.28 (d, J = 6.5 Hz, 1H), 1.38 (s, 9H). A  36

6-(tert-butylsulfonyl)-N- (4,5-dimethyl-1H-pyrazol-3-yl)-7-methylquinolin-4- amine 373 ¹H NMR (DMSO-d₆) 12.27 (br s, 1H),9.37 (br s, 1H), 8.98 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H),6.49 (d, J = 5.1 Hz, 1H), 2.75 (s, 3H), 2.20 (s, 3H), 1.78 (s, 3H), 1.32(s, 9H). A 397

6-(tert-butylsulfonyl)-N-(5- fluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine 413 ¹H NMR (DMSO-d₆) 13.00 (s, 1H), 9.96 (s, 1H),9.12 (s, 1H), 8.57 (d, J = 5.3 Hz, 1H), 7.90 (s, 1H), 7.60 (dd, J = 8.8,4.0 Hz, 1H), 7.48 (dd, J = 9.1, 1.8 Hz, 1H), 7.32 (td, J = 9.1, 2.3 Hz,1H), 7.12 (d, J = 5.3 Hz, 1H), 2.79 (s, 3H), 1.34 (s, 9H). A  38

6-(tert-butylsulfonyl)-N-(5- fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine 429 ¹H NMR (DMSO-d₆) 12.96 (br s, 1H), 9.91 (brs, 1H), 9.06 (s, 1H), 8.47-8.58 (m, 1H), 7.58 (dd, J = 9.0, 4.2 Hz, 1H),7.45-7.54 (m, 2H), 7.31 (td, J = 9.0, 2.1 Hz, 1H), 7.06 (d, J = 5.3 Hz,1H), 3.98 (s, 3H), 1.34 (s, 9H). A  39

6-(tert-butylsulfonyl)-7- chloro-N-(5-fluoro-1H-indazol-3-yl)quinolin-4- amine 433 ¹H NMR (DMSO-d6) Shift: 9.28 (s, 1H),8.54 (br. s., 1H), 8.05 (br. s., 1H), 7.59 (dd, J = 8.5, 4.0 Hz, 1H),7.41-7.51 (m, 1H), 7.27-7.36 (m, 1H), 7.17 (d, J = 5.3 Hz, 1H), 1.39 (s,9H) A  40

6-(tert-butylsulfonyl)-7- ethyl-N-(5-fluoro-1H- indazol-3-yl)quinolin-4-amine 427 ¹H NMR (DMSO-d6) Shift: 12.98 (br. s., 1H), 9.12 (s, 1H), 8.54(br. s., 1H), 7.91 (br. s., 1H), 7.59 (dd, J = 9.0, 4.2 Hz, 1H),7.42-7.51 (m, 1H), 7.31 (td, J = 9.0, 2.2 Hz, 1H), 7.11 (d, J = 5.6 Hz,1H), 3.19 (q, J = 7.3 Hz, 2H), 1.26-1.37 (m, 12H) A  41

N-(5-fluoro-1H-indazol-3- yl)-6-(isopropyl-sulfonyl)-7-methylquinolin-4-amine 399 ¹H NMR (DMSO-d6) Shift: 9.51 (s, 1H), 9.06(d, J = 6.1 Hz, 1H), 8.18 (s, 1H), 7.91 (d, J = 5.8 Hz, 1H), 7.83-7.90(m, 2H), 7.49 (td, J = 9.1, 2.5 Hz, 1H), 3.63 (quin, J = 6.8 Hz, 1H),2.85 (s, 3H), 1.21 (d, J = 6.8 Hz, 6H) A  42

N-(4,5-dimethyl-1H- pyrazol-3-yl)-6-(isopropyl-sulfonyl)-7-methylquinolin- 4-amine 359 ¹H NMR (DMSO-d6) Shift: 12.40(br. s., 1H), 9.09 (s, 1H), 8.49 (d, J = 6.1 Hz, 1H), 7.86 (s, 1H),6.52-6.68 (m, 1H), 3.59 (quin, J = 6.8 Hz, 1H), 2.77 (s, 3H), 2.21 (s,3H), 1.81 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H) A  43

6-(tert-butylsulfonyl)-N- (4,5-dimethyl-1H-pyrazol-3-yl)-7-ethylquinolin-4- amine 387 ¹H NMR (DMSO-d6) Shift: 12.45 (br.s., 1H), 9.08 (s, 1H), 8.50 (d, J = 6.0 Hz, 1H), 7.90 (s, 1H), 6.56 (d,J = 5.5 Hz, 1H), 3.18 (q, J = 7.3 Hz, 2H), 2.22 (s, 3H), 1.80 (s, 3H),1.22-1.42 (m, 12H) A  44

7-ethyl-N-(5-fluoro-1H- indazol-3-yl)-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 455 ¹H NMR (DMSO-d6) Shift: 9.29 (s, 1H),8.63 (d, J = 6.6 Hz, 1H), 8.01 (s, 1H), 7.66 (dd, J = 9.0, 4.2 Hz, 1H),7.56 (dd, J = 9.0, 2.0 Hz, 1H), 7.37 (td, J = 9.0, 2.2 Hz, 1H), 7.19 (d,J = 6.6 Hz, 1H), 3.89-3.99 (m, 2H), 3.64-3.77 (m, 1H), 3.30-3.40 (m,2H), 3.24 (q, J = 7.2 Hz, 2H), 1.65-1.79 (m, 4H), 1.37 (t, 3H) A  45

N-(4,5-dimethyl-1H- pyrazol-3-yl)-7-ethyl-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 415 ¹H NMR (DMSO-d6) Shift: 12.29 (br. s.,1H), 9.33 (br. s., 1H), 8.99 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.87 (s,1H), 6.53 (d, J = 4.5 Hz, 1H), 3.86-4.01 (m, 2H), 3.54-3.68 (m, 1H),3.28-3.34 (m, 2H), 3.15 (q, J = 7.3 Hz, 2H), 2.21 (s, 3H), 1.80 (s, 3H),1.65-1.76 (m, 4H), 1.34 (t, 3H) A  46

(3-((6-(tert-butylsulfonyl)- 7-methoxyquinolin-4- yl)amino)-4-methylphenyl)methanol 415 ¹H NMR (DMSO-d6) Shift: 9.38 (s, 1H), 8.95 (s,1H), 8.37 (d, J = 5.3 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H),7.18-7.23 (m, 2H), 6.00 (d, J = 5.6 Hz, 1H), 5.20 (t, J = 5.7 Hz, 1H),4.50 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H), 2.13 (s, 3H), 1.32 (s, 9H) A  47

N-(5-chloro-1H-indazol-3- yl)-7-methoxy-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 473 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.04(s, 1H), 9.14 (s, 1H), 8.56 (d, J = 5.56 Hz, 1H), 7.99 (d, J = 1.52 Hz,1H), 7.59 (d, J = 8.84 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 1.77 Hz, 1H),7.42 (d, J = 2.02 Hz, 1H). 7.37 (d, J = 5.81 Hz, 1H), 4.09 (s, 3H),3.92-3.97 (m, 2H), 3.81-3.90 (m, 1H), 3.30-3.41 (m, 2H), 1.64-1.79 (m,4H) B  48

7-ethoxy-N-(5-fluoro-1H- indazol-3-yl)-6-(isopropyl-sulfonyl)quinolin-4-amine 429 ¹H NMR (DMSO-d6) Shift: 12.86 (s, 1H),9.86 (s, 1H), 9.05 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 7.61 (dd, J =11.9, 2.0 Hz, 1H), 7.53-7.58 (m, 1H), 7.31 (td, J = 9.1, 2.3 Hz, 1H),7.20 (d, J = 5.6 Hz, 1H), 4.36 (q, J = 6.8 Hz, 2H), 3.83 (m, 1H), 1.45(t, J = 6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H) B  49

N-(7-Chloro-1H-indazol-3- yl)-7-methoxy-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 473 ¹H NMR (400 MHz, DMSO-d₆) δ 1.67-1.75(m, 4H) 3.34-3.42 (m, 2H) 3.79-3.89 (m, 1H) 3.90-3.98 (m, 2H) 4.07 (s,3H), 7.14 (t, J = 7.83 Hz, 1H) 7.29 (d, J = 5.56 Hz, 1H) 7.51 (s, 1H)7.53 (s, 1H) 7.83 (d, J = 8.08 Hz, 1H) 8.56 (d, J = 5.31 Hz, 1H) 9.10(s, 1H) 10.02 (s, 1H) 13.30 (s, 1H) B  50

6-(tert-butylsulfonyl)-N-(7- fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine 429 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.47 (br.s., 1H), 10.05 (br. s., 1H), 9.07 (s, 1H), 8.43-8.56 (m, 1H), 7.56 (d, J= 8.08 Hz, 1H), 7.46 (br. s., 1H), 7.25 (dd, J = 7.71, 11.49 Hz, 1H),7.01-7.14 (m, 2H), 3.98 (s, 3H), 1.33 (s, 9H) A  51

6-(tert-butylsulfonyl)-N- (5,7-difluoro-1H-indazol-3-yl)-7-methoxyquinolin-4- amine 447 ¹H NMR (400 MHz, DMSO-d6) Shift:13.08-13.89 (m, 1H), 9.96 (br. s., 1H), 9.04 (s, 1H), 8.52 (br. s., 1H),7.47 (br. s., 1H), 7.31-7.43 (m, 2H), 7.07 (d, J = 4.55 Hz, 1H), 3.98(s, 3H), 1.33 (s, 9H) A  52

6-(tert-butylsulfonyl)-N- (6,7-difluoro-1H-indazol-3-yl)-7-methoxyquinolin-4- amine 447 ¹H NMR (400 MHz, DMSO-d6) Shift:13.50 (s, 1H), 10.02 (s, 1H), 9.06 (s, 1H), 8.57 (d, J = 5.56 Hz, 1H),7.64 (dd, J = 3.92, 8.72 Hz, 1H), 7.50 (s, 1H), 7.09-7.32 (m, 2H), 3.99(s, 3H), 1.33 (s, 9H) A  53

6-(tert-butylsulfonyl)-N-(7- chloro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine 445 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.35 (s,1H), 10.04 (s, 1H), 9.07 (s, 1H), 8.54 (d, J = 5.31 Hz, 1H), 7.75 (d, J= 8.08 Hz, 1H), 7.41-7.58 (m, 2H), 7.07-7.20 (m, 2H), 3.99 (s, 3H), 1.33(s, 9H) A  54

6-(tert-butylsulfonyl)-7- methoxy-N-(5- methoxy-1H-indazol-3-yl)quinolin-4-amine 441 ¹H NMR (400 MHz, DMSO-d6) Shift: 12.75 (s, 1H),9.97 (br. s., 1H), 9.07 (s, 1H), 8.47 (br. s., 1H), 7.42-7.50 (m, 2H),6.99-7.11 (m, 2H), 6.83 (d, J = 5.56 Hz, 1H), 3.98 (s, 3H), 3.74 (s,3H), 1.34 (s, 9H) A  55

6-(tert-butylsulfonyl)-N-(7- fluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine 413 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.43 (s,1H), 10.08 (s, 1H), 9.13 (s, 1H), 8.59 (d, J = 5.56 Hz, 1H), 7.91 (s,1H), 7.55 (d, J = 8.08 Hz, 1H), 7.27 (dd, J = 7.58, 11.37 Hz, 1H), 7.17(d, J = 5.56 Hz, 1H), 7.10 (td, J = 4.55, 7.83 Hz, 1H), 2.79 (s, 3H),1.34 (s, 9H) A  56

6-(tert-butylsulfonyl)-N- (5,7-difluoro-1H-indazol-3-yl)-7-methylquinolin-4- amine 431 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.58(br. s., 1H), 10.00 (s, 1H), 9.11 (s, 1H), 8.60 (d, J = 5.31 Hz, 1H),7.91 (s, 1H), 7.40 (d, J = 7.83 Hz, 2H), 7.15 (d, J = 5.05 Hz, 1H), 2.79(s, 3H), 1.34 (s, 9H) A  57

6-(tert-butylsulfonyl)-N-(5- methoxy-1H-indazol-3-yl)-7-methylquinolin-4-amine 425 ¹H NMR (400 MHz, DMSO-d6) Shift: 12.78 (s,1H), 9.96 (s, 1H), 9.13 (s, 1H), 8.53 (d, J = 5.56 Hz, 1H), 7.88 (s,1H), 7.48 (d, J = 9.09 Hz, 1H), 7.08 (dd, J = 2.40, 8.97 Hz, 1H), 6.99(d, J = 2.02 Hz, 1H), 6.89 (d, J = 5.56 Hz, 1H), 3.73 (s, 3H), 2.79 (s,3H), 1.35 (s, 9H) A  58

6-(tert-butylsulfonyl)-N- (6,7-difluoro-1H-indazol-3-yl)-7-methylquinolin-4- amine 431 ¹H NMR (400 MHz, DMSO-d6) Shift: 9.12(s, 1H), 8.52 (br. s., 1H), 7.85 (br. s., 1H), 7.58 (dd, J = 3.92, 8.72Hz, 1H), 7.27 (d, J = 5.56 Hz, 1H), 7.16 (ddd, J = 6.69, 8.91, 10.67 Hz,1H), 2.78 (s, 3H), 1.33 (s, 9H) A  59

6-(tert-butylsulfonyl)-N-(7- chloro-1H-indazol-3-yl)-7-methylquinolin-4-amine 429 ¹H NMR (400 MHz, DMSO-d6) Shift: 9.13 (s,1H), 8.54 (br. s., 1H), 7.87 (br. s., 1H), 7.70 (d, J = 8.08 Hz, 1H),7.50 (d, J = 7.07 Hz, 1H), 7.19 (d, J = 5.31 Hz, 1H), 7.12 (t, J = 7.83Hz, 1H), 2.78 (s, 3H), 1.34 (s, 9H) A  60

7-methoxy-N-(4-methyl-5- (trifluoromethyl)-1H- pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4- yl)sulfonyl)quinolin-4- amine 471 ¹H NMR (400MHz, DMSO-d6) Shift: 13.70 (br. s., 1H), 8.98 (br. s., 1H), 8.46 (br.s., 1H), 7.39-7.57 (m, 1H), 6.19 (br. s., 1H), 4.07 (s, 3H), 3.90-3.99(M, 2H), 3.79-3.90 (m, 1H), 3.36 (m, 2H), 1.95 (s, 3H), 1.61-1.77 (m,4H) B  61

N-(5,7-difluoro-1H- indazol-3-yl)-7-methoxy-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 475 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.40(br. s., 1H), 9.97 (br. s., 1H), 9.07 (s, 1H), 8.52 (br. s., 1H),7.45-7.55 (m, 2H), 7.33-7.43 (m, 1H), 7.21 (d, J = 5.31 Hz, 1H), 4.07(s, 3H), 3.89-4.00 (m, 2H), 3.77-3.89 (m, 1H), 3.28-3.43 (m, 2H),1.65-1.76 (m, 4H) B  62

N-(4-chloro-1H-indazol-3- yl)-7-methoxy-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-1- amine 473 ¹H NMR (400 MHz, DMSO-d6) Shift: 13.26(br. s., 1H), 9.72 (br. s., 1H), 9.01 (s, 1H), 8.42 (br. s., 1H), 7.55(d, J = 8.34 Hz, 1H), 7.49 (br. s., 1H), 7.38 (t, J = 7.96 Hz, 1H), 7.16(d, J = 7.33 Hz, 1H), 6.40 (d, J = 5.05 Hz, 1H), 4.06 (s, 3H), 3.89-3.98(m, 2H), 3.75-3.88 (m, 1H), 3.37 (d, J = 3.03 Hz, 2H), 1.63-1.77 (m, 4H)B  63

N-(6-chloro-1H-indazol-3- yl)-7-methoxy-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 473 ¹H NMR (400 MHz, DMSO-d6) Shift: 12.89(br. s., 1H), 10.00 (br. s., 1H), 9.09 (s, 1H), 8.55 (br. s., 1H), 7.88(d, J = 8.84 Hz, 1H), 7.59-7.61 (m, 1H), 7.52 (br. s., 1H), 7.35 (d, J =4.80 Hz, 1H), 7.15 (dd, J = 1.64, 8.72 Hz, 1H), 4.07 (s, 3H), 3.90-3.97(m, 2H), 3.79-3.88 (m, 1H), 3.33-3.41 (m, 2H), 1.62-1.75 (m, 4H) B  64

N-(6,7-difluoro-1H- indazol-3-yl)-7-methoxy-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 475 ¹H NMR (400 MHz, DMSO-d6) Shift:12.79-13.69 (m, 1H), 9.92 (br. s., 1H), 9.08 (s, 1H), 8.55 (br. s., 1H),7.61-7.75 (m, 1H), 7.45-7.55 (m, 1H), 7.28-7.39 (m, 1H), 7.05-7.23 (m,1H), 4.07 (s, 3H), 3.94 (d, J = 10.86 Hz, 2H), 3.77-3.89 (m, 1H),3.29-3.40 (m, 2H), 1.62-1.76 (m, 4H) B  65

7-methoxy-N-(5-methoxy- 1H-indazol-3-yl)-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 469 NA B

Example 66 N-1,3-benzothiazol-5-yl-6-(methylsulfonyl)-4-quinolinamine

Step 1:5-({[3-bromo-4-(methylsulfonyl)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione:A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.7 g, 12 mmol) andtrimethyl orthoformate (24 mL) was heated at reflux for 2 h at whichtime 3-bromo-4-(methylsulfonyl)aniline (3 g, 12 mmol) was added. Thereaction was stirred at 105° C. for 1 hour, cooled to room temperatureand filtered. The filter cake was washed with MeOH and dried to provide5-({[3-bromo-4-(methylsulfonyl)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(3.5 g, 8.66 mmol, 72.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.31(s, 1H), 8.68 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),7.85 (dd, J=8.8, 2.3 Hz, 1H), 3.38 (s, 3H), 1.69 (s, 6H). MS (m/z) 404,406 (M+H)

Step 2: 7-bromo-6-(methylsulfonyl)-4-quinolinol: To a 3-neck flaskcontaining diphenylether (17 mL) at 240° C. was added5-({[3-bromo-4-(methylsulfonyl)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(3.5 g, 8.6 mmol). After the addition was complete, the reaction wasallowed to cool to rt, diluted with hexanes and filtered. The crudeproduct was dissolved in DCM, dry loaded onto silica, and purified viacolumn chromatography (Biotage, 0-20% MeOH, EtOAc). The desiredfractions were concentrated to yield7-bromo-6-(methylsulfonyl)-4-quinolinol (800 mg, 2.7 mmol, 31% yield).¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.09 (br. s., 1H), 8.73 (s, 1H),7.92-8.10 (m, 2H), 6.18 (d, J=7.6 Hz, 1H), 3.40 (s, 3H). MS (m/z) 302,304 (M+H)

Step 3: 7-bromo-4-chloro-6-(methylsulfonyl)quinoline: A mixture of7-bromo-6-(methylsulfonyl)-4-quinolinol (800 mg, 2.65 mmol) andphosphorus oxychloride (12.300 mL, 132 mmol) was heated at 110° C. After2 h, the reaction was cooled to rt and concentrated to dryness. Theresidue was carefully treated with saturated sodium bicarbonate solutionuntil all of the residual POCl₃ was neutralized. The mixture wasfiltered and the precipitate was dried and isolated to provide7-bromo-4-chloro-6-(methylsulfonyl)quinoline (690 mg, 2.1 mmol, 81%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.07 (d, J=4.8 Hz, 1H), 8.91 (s,1H), 8.66 (s, 1H), 8.02 (d, J=4.8 Hz, 1H), 3.53 (s, 3H). MS (m/z) 320,322 (M+H)

Step 4:N-1,3-benzothiazol-5-yl-7-bromo-6-(methylsulfonyl)-4-quinolinamine:7-bromo-4-chloro-6-(methylsulfonyl)quinoline (500 mg, 1.6 mmol),1,3-benzothiazol-5-amine (234 mg, 1.56 mmol), and EtOH (3.1 mL) werecombined and heated in the microwave at 150° C. for 10 min. The reactionwas concentrated to dryness to provideN-1,3-benzothiazol-5-yl-7-bromo-6-(methylsulfonyl)-4-quinolinamine asthe HCl salt in quantitative yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.69 (br. s., 1H), 9.55 (s, 1H), 9.48 (s, 1H), 8.54-8.63 (m, 2H), 8.40(d, J=8.6 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.61 (dd, J=8.6, 2.0 Hz, 1H),6.97 (d, J=6.8 Hz, 1H), 3.54 (s, 3H). MS (m/z) 434, 436 (M+H)

The following examples were synthesized in the same manner as the aboveexample using the appropriate quinoline from the above preparationsand/or commercially available materials.

MS Ex. Structure Name (M + H)⁺ NMR 67

7-bromo-N-(4,5-dimethyl- 1H-pyrazol-3-yl)-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine, 2 Trifluoroacetic acid salt 465 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.73 (br. s., 1H), 11.43 (br. s., 1H), 9.39(br. s., 1H), 8.62 (d, J = 7.1 Hz, 1H), 8.40 (s, 1H), 6.85 (d, J = 7.1Hz, 1H), 3.82-4.05 (m, 3H), 3.23-3.45 (m, 2H), 2.25 (s, 3H), 1.86 (s,3H), 1.67-1.81 (m, 4H) 68

7-bromo-6-(tert- butylsulfonyl)-N-(4,5- dimethyl-1H-pyrazol-3-yl)quinolin-4-amine, (2 Trifluoroacetic acid salt) 437 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.58-12.89 (m, 1H), 11.50 (br. s., 1H), 9.40 (br. s.,1H), 8.61 (d, J = 7.1 Hz, 1H), 8.37 (s, 1H), 6.80 (d, J = 7.1 Hz, 1H),2.25 (s, 3H), 1.85 (s, 3H), 1.40 (s, 9H) 69

7-bromo-N-(4-methyl-5- (trifluoromethyl)-1H- pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4- yl)sulfonyl)quinolin-4- amine  519, 521 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 13.75 (br. s., 1H), 9.66-10.04 (m, 1H),8.99-9.37 (m, 1H), 8.49-8.85 (m, 1H), 8.27-8.45 (m, 1H), 6.36 (br. s.,1H), 3.84-4.13 (m, 4H), 3.22-3.52 (m, 1H), 1.96 (s, 3H), 1.74 (d, J =2.78 Hz, 1H) 70

7-bromo-N-(4,5-dimethyl- 1H-pyrazol-3-yl)-6-(isopropylsulfonyl)quinolin- 4-amine 423 ¹H NMR (DMSO-d6) Shift: 12.25(br. s., 1H), 9.53 (br. s., 1H), 9.15 (br. s., 1H), 8.41-8.62 (m, 1H),8.15-8.37 (m, 1H), 6.50-6.77 (m, 1H), 3.81-3.97 (m, 1H), 2.18 (br. s.,3H), 1.78 (br. s., 3H), 1.25 (d, J = 6.8 Hz, 6H) 71

7-bromo-N-(5-fluoro-1H- indazol-3-yl)-6- (isopropylsulfonyl)quinolin-4-amine 463 ¹H NMR (DMSO-d6) Shift: 9.29 (s, 1H), 8.45 (s, 1H), 8.20(br. s., 1H), 7.43-7.61 (m, 2H), 7.19-7.35 (m, 2H), 3.86-4.00 (m, 1H),1.27 (d, J = 6.8 Hz, 6H) 72

7-bromo-N-(5-fluoro-1H- indazol-3-yl)-6- ((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4- amine 505 NA

Example 73N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine

Step 1.N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)-4-quinolinamine:4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline (0.20 g,0.66 mmol) and 1,3-benzothiazol-5-amine (0.10 g, 0.66 mmol) inisopropanol (2 mL) were irradiated by microwave at 150° C. for 15 mins.The reaction mixture was concentrated, purified via flash chromatography(0-50% EtOAc/Hexane, 0-5% MeOH/DCM) to yieldN-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)-4-quinolinamine(0.26 g, 0.67 mmol, 94% yield). ¹H NMR (400 MHz, DMSO-d) δ ppm 1.28 (s,9H), 3.93 (s, 3H), 6.90 (d, J=5.3 Hz, 1H), 7.32 (s, 1H), 7.54 (dd, J=8.6Hz, 2 Hz, 1H), 8.02 (d, J=2 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 8.42 (d,J=5.3 Hz, 1H), 8.60 (s, 1H), 9.27 (s, 1H), 9.42 (s, 1H). MS (m/z) 396(M+H⁺).

Step 2.N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine:N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)-4-quinolinamine(0.14 g, 0.34 mmol) and oxone (0.32 g, 0.52 mmol) in MeOH (2 mL) andwater (2 mL) were stirred at room temperature. The reaction mixture wasfiltered, and the cake was washed with MeOH. The filtrate wasconcentrated, dissolved in dimethyl sulfoxide, purified via reversephase HPLC (Waters SunFire Prep C18 OBD 5 μm, 30×100 mm column, 20-30%acetonitrile/water 0.1% TFA, 40 mL/min, 10 min) to yield thetrifluoroacetic acid salt. The salt was basified with saturated sodiumcarbonate and extracted with EtOAc. The EtOAc layer was dried oversodium sulfate, filtered, concentrated and vacuum dried to yieldN-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine(0.040 g, 0.091 mmol, 26.6% yield). ¹H NMR (400 MHz, DMSO-d) δ ppm 1.32(s, 9H), 3.98 (s, 3H), 6.90 (d, J=5.3 Hz, 1H), 7.47 (s, 1H), 7.54 (dd,J=8.6 Hz, 2 Hz, 1H), 8.03 (d, J=2 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.50(d, J=5.6 Hz, 1H), 8.94 (s, 1H), 9.43 (s, 1H), 9.69 (s, 1H). MS (m/z)428 (M+H⁺).

Example 742-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-yl)oxy)ethanol

A suspension of6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-ol(50.0 mg, 0.134 mmol) and potassium carbonate (55.4 mg, 0.401 mmol) inDMF (0.65 mL) was stirred 2 min before 2-bromoethanol (47.3 μA, 0.668mmol) was added. The reaction mixture was stirred at room temperaturefor 3 d. The crude reaction mixture was filtered and the residue waspurified via Gilson reverse phase chromatography (6% to 75% 0.1% TFA inMeCN in 0.1% TFA in water; Sum 30×150 mm Waters SunFire column). Thecollected fractions were evaporated to dryness to provide2-(6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-yl)oxy)ethanol(15.6 mg, 22% yield) as a colorless oil. ¹H NMR (METHANOL-d₄) δ ppm 9.23(br. s., 1H), 8.38 (d, J=7.3 Hz, 1H), 7.50 (s, 1H), 6.76 (d, J=7.3 Hz,1H), 4.39 (t, J=4.5 Hz, 2H), 4.04 (dd, J=5.1, 4.3 Hz, 2H), 2.33 (s, 3H),1.96 (s, 3H), 1.47 (s, 9H). MS (m/z) 418, 419 (M+H⁺).

Example 756-(tert-butylsulfonyl)-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine

Step 1. 6-bromo-4-chloroquinolin-7-ol:6-Bromo-4-chloro-7-methoxyquinoline (5 g, 18.4 mmol) was taken up in DCE(15 mL) before BBr₃ (5.20 mL, 55.0 mmol) was added dropwise. Reactionwas then heated to 100° C. via microwave for 2 hours. The reaction wascarefully pipetted into stirred MeOH. The suspension was thenconcentrated. It was then taken up in 50 mL of MeOH and filtered. Thecake was rinsed with MeOH once and dried under vacuum to afford thetitle compound (4.82 g, 99%). MS (m/z): 258, 260 (M+H⁺).

Step 2. 6-bromo-4-chloro-7-(difluoromethoxy)quinoline: To a DMF (15 mL)solution of 6-bromo-4-chloroquinolin-7-ol (3 g, 11.6 mmol) was addedcesium carbonate (11.34 g, 34.8 mmol). After 30 min, methyl2-chloro-2,2-difluoroacetate (2.5 mL, 23.2 mmol) was added and thereaction was heated to 80° C. overnight. It was cooled to rt andconcentrated. The residue was suspended in DCM and filtered. Thefiltrate was concentrated. The resulting crude was purified by flashchromatography to afford the product as a light brown solid (750 mg,20%). MS (m/z): 308, 310 (M+H⁺).

Step 3.6-bromo-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine:6-Bromo-4-chloro-7-(difluoromethoxy)quinoline (750 mg, 2.4 mmol) and4,5-dimethyl-1H-pyrazol-3-amine (270 mg, 2.4 mmol) were taken up in NMP(5 mL) before 2 drops of conc HCl was added. The reaction was heated to80° C. overnight before being concentrated. The residue was thensuspended in 5 mL of DCM, sonicated, and filtered. The solid was washedwith DCM and the desired product was obtained as a yellow solid (820 mg,84%). MS (m/z): 383, 385 (M+H⁺).

Step 4.6-(tert-butylthio)-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine:To a vial was added6-bromo-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine(410 mg, 1.07 mmol), Pd₂ dba₃ (98 mg, 0.11 mmol), Xantphos (61.9 mg,0.11 mmol), and sodium carbonate (284 mg, 2.67 mmol) before evacuatingand backfilling the vial with nitrogen. 1,4-Dioxane (5000 μl) was thenadded followed by t-butylthiol (133 μl, 1.18 mmol). The reaction wasthen heated to 95° C. overnight. Additional heating in the microwave for30 min at 120° C. allowed the reaction to go to completion. The reactionmixture was purified by flash chromatography to afford the product asyellow-brown solid (430 mg, 97%). MS (m/z): 393 (M+H⁺).

Step 5.6-(tert-butylsulfonyl)-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine:6-(tert-Butylthio)-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine(430 mg, 1.10 mmol) was taken up in EtOAc (6 mL) and water (6 mL) beforeoxone (775 mg, 1.26 mmol) was added and the reaction was stirred at rtover the weekend. The reaction was concentrated. The residue was thendissolved in DMSO:MeOH (5 mL), filtered through a syringe filter, andpurified by reverse phase HPLC. Purified material was dissolved in MeOHand free based using a MP-carbonate resin. After allowing the mixture tosit on the resin overnight, the resin was filtered off, and rinsed withMeOH. The filtrate was then concentrated to afford the title product asa yellow solid (164 mg, 32%). ¹H NMR (DMSO-d₆) δ 12.51 (br. s., 1H),10.44 (br. s., 1H), 9.21 (s, 1H), 8.55 (d, J=6.3 Hz, 1H), 7.72 (s, 1H),7.49 (t, J=73 Hz, 1H), 6.64 (d, J=6.1 Hz, 1H), 2.23 (s, 3H), 1.82 (s,3H), 1.36 (s, 9H); MS (m/z): 425 (M+H⁺).

The following examples were synthesized in the same manner as the aboveexample.

MS Ex. Structure Name (M + H)⁺ NMR 76

7- (difluoromethoxy)- N-(4,5-dimethyl- 1H-pyrazol-3-yl)-6-((tetrahydro-2H- pyran-4- yl)sulfonyl)quinolin- 4-amine 453 ¹H NMR(DMSO-d6) Shift: 12.30 (br. s., 1H), 9.53 (br. s., 1H), 9.10 (s, 1H),8.50 (d, J = 5.6 Hz, 1H), 7.68 (s, 1H), 7.56 (t, J = 72.8 Hz, 1H), 6.59(d, J = 4.8 Hz, 1H), 3.90-4.00 (m, 2H), 3.62-3.76 (m, 1H), 3.28-3.40 (m,2H), 2.21 (s, 3H), 1.80 (s, 3H), 1.66-1.78 (m, 4H)

Example 772-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethanol

Step 1. 2-((6-bromo-4-chloroquinolin-7-yl)oxy)ethanol: To a THF (20 mL)solution of 6-bromo-4-chloroquinolin-7-ol (1000 mg, 3.87 mmol) was addedNaH (232 mg, 5.80 mmol, 60% in mineral oil) at rt. The mixture wasstirred for 30 min before 2-bromoethanol (0.33 mL, 4.64 mmol) was addedand the reaction was heated to 80° C. overnight. It was then cooled tort and concentrated. The crude was purified by flash chromatography toafford the product as a yellow solid (970 mg, 83%). MS (m/z): 302, 304(M+H⁺).

Step 2.2-((4-(benzo[d]thiazol-5-ylamino)-6-bromoquinolin-7-yl)oxy)ethanol:2-((6-bromo-4-chloroquinolin-7-yl)oxy)ethanol (0.97 g, 3.21 mmol),benzo[d]thiazol-5-amine (0.58 g, 3.85 mmol), 1,4-dioxane (5 mL), and 2drops of conc. HCl were combined and heated to 150° C. for 30 min viamicrowave. It was concentrated onto silica gel and purified by flashchromatography. The title compound was obtained as a yellow solid (560mg, 40%). MS (m/z): 416, 418 (M+H⁺).

Step 3.2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylthio)quinolin-7-yl)oxy)ethanol:To a vial was added2-((4-(benzo[d]thiazol-5-ylamino)-6-bromoquinolin-7-yl)oxy)ethanol (100mg, 0.24 mmol), Pd₂ dba₃ (22 mg, 0.02 mmol), Xantphos (14 mg, 0.02mmol), and sodium carbonate (64 mg, 0.60 mmol). The vial was evacuatedand backfilled with nitrogen three times before 1,4-dioxane (1 mL) andthen tert-butylthiol (30 μl, 0.26 mmol) were added. The reaction washeated to 90° C. overnight. It was cooled to rt and quenched with 2 mLof sat aq NH₄Cl. The mixture was extracted using EtOAc (3×5 mL) and thecombined organics were dried over sodium sulfate, filtered, andconcentrated. The crude was then purified by flash chromatography whichafforded the product as a yellow film (90 mg, 84). MS (m/z): 426.1(M+H⁺).

Step 4.2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethanol:2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylthio)quinolin-7-yl)oxy)ethanol(90 mg, 0.21 mmol) was dissolved in MeOH (3 mL) before water (3 mL) andthen oxone (130 mg, 0.21 mmol) were added. The reaction mixture wasstirred at rt overnight. It was concentrated and the residue was takenup in 2 mL of 1:1 DMSO:MeOH, filtered through a syringe filter, andpurified by reverse phase HPLC to afford the title compound (42 mg,43%). ¹H NMR (DMSO-d₆) δ 9.83 (br. s., 1H), 9.45 (s, 1H), 8.97 (s, 1H),8.49 (d, J=5.5 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H),7.55 (dd, J=8.7, 1.6 Hz, 1H), 7.48 (s, 1H), 6.89 (d, J=5.5 Hz, 1H), 4.80(br. s., 1H), 4.25 (t, J=5.0 Hz, 2H), 3.82 (d, J=4.5 Hz, 2H), 1.35 (s,9H); MS (m/z): 458 (M+H⁺).

Example 78(3-((6-(tert-Butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazol-5-yl)methanol

Step 1: Ethyl3-{[6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinyl]amino}-4-methyl-1H-pyrazole-5-carboxylate,Hydrochloride: 6-(tert-Butylsulfonyl)-4-chloro-7-methoxyquinoline (420mg, 1.338 mmol) and ethyl 3-amino-4-methyl-1H-pyrazole-5-carboxylate(249 mg, 1.472 mmol) were dissolved in EtOH with two drops of HCl (4M indioxane) added, and the reaction mixture was heated at 80° C. for 5 hfollowed by then cooling to room temperature. The precipitate wasfiltered, washed with EtOH, and air dried to give ethyl3-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazole-5-carboxylate,Hydrochloride (586 mg, 1.213 mmol, 91% yield) as a yellow solid. ¹H NMR(DMSO-d₆) δ: 1.31-1.38 (m, 12H) 2.13 (s, 3H) 4.04 (s, 3H) 4.37 (q,J=7.07 Hz, 2H) 6.62 (d, J=6.82 Hz, 1H) 7.71 (s, 1H) 8.55 (d, J=7.07 Hz,1H) 9.24 (br. s., 1H) 11.33 (br. s., 1H) 14.10 (br. s., 1H) 14.76 (br.s., 1H)); MS (m/z) 447 (M+H⁺).

Step 2:(3-((6-(tert-Butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazol-5-yl)methanol:Ethyl3-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazole-5-carboxylate,Hydrochloride (100 mg, 0.207 mmol) was suspended in THF (2 mL) andlithium aluminum hydride (1.0 M in THF, 0.518 mL, 0.518 mmol) was addeddropwise. The reaction mixture was stirred at room temperature for 4 hbefore quenching with water (0.1 mL), NaOH (2N, 0.1 mL), and NH₄Cl(sat'd, 0.4 mL) sequentially. The mixture was extracted with DCM (2×50mL). The combined organics were dried over MgSO₄, filtered, andconcentrated before and purifying on an ISCO (silica gel column, 10 g)using 10-20% of (10% ammonium hydroxide in IPA) in EtOAc to afford thedesired product(3-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazol-5-yl)methanolas off-white solid (16 mg, 0.040 mmol, 19.11% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 1.32 (s, 9H) 1.84 (s, 3H) 3.96 (s, 3H) 4.48 (d, J=5.31 Hz,2H) 5.21 (t, J=5.56 Hz, 1H) 6.41 (d, J=5.56 Hz, 1H) 7.41 (s, 1H) 8.41(d, J=5.56 Hz, 1H) 8.95 (s, 1H) 9.36 (br. s., 1H) 12.48 (br. s., 1H); MS(m/z) 405 (M+H⁺).

Example 79N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine

Step 1:4-chloro-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinoline: To anoven dried RBF was added4-chloro-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinoline (450mg, 1.381 mmol) and THF (18 mL). The solution was cooled to −78° C. andLHMDS (4.14 mL, 4.14 mmol) was added. After 15 min, methyl iodide (0.345mL, 5.52 mmol) was added and the reaction was allowed to warm to rt over2 h. Saturated ammonium chloride was added and the reaction wasextracted with DCM (2×), washed with brine (1×) and dry-loaded ontosilica gel. The crude product was purified via column chromatography(Biotage SP-1 0-15% MeOH/EtOAc, 50 g column) to afford4-chloro-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinoline(125 mg, 0.305 mmol, 22.10% yield) which was only 83% pure, but carriedon as is to the next step. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.02 (d,J=4.5 Hz, 1H), 8.66 (s, 1H), 8.20 (s, 1H), 7.91 (d, J=4.8 Hz, 1H),3.72-3.86 (m, 2H), 3.45 (td, J=11.9, 1.8 Hz, 2H), 2.77-2.91 (m, 3H),1.90-2.11 (m, 2H), 1.51 (d, J=13.6 Hz, 2H), 1.43 (s, 3H). MS (m/z) 340.

Step 2:N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine:A mixture of4-chloro-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinoline(50 mg, 0.122 mmol) and 4,5-dimethyl-1H-pyrazol-3-amine (16.29 mg, 0.147mmol) in EtOH (1221 μl) was treated with 1 drop of conc. HCl (0.122mmol) and heated to 70° C. for 3 d. The reaction was diluted with waterand DMSO, filtered, and the filtrate was concentrated and purified viareverse phase HPLC (10-60% acetonitrile/water w/0.1% TFA). Theproduct-containing fractions were concentrated to dryness and theresulting oil was treated with EtOAc/hexane and concentrated to drynessto affordN-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine,2 Trifluoroacetic acid salt (10 mg, 0.016 mmol, 12.74% yield) as asolid. NMR: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 14.25 (br. s., 1H), 12.71(br. s., 1H), 11.28 (br. s., 1H), 9.23 (br. s., 1H), 8.56 (d, J=7.1 Hz,1H), 7.91 (s, 1H), 6.74 (d, J=7.1 Hz, 1H), 3.84 (dd, J=11.6, 4.3 Hz,2H), 3.44-3.53 (m, 2H), 2.85 (s, 3H), 2.25 (s, 3H), 2.01-2.18 (m, 2H),1.85 (s, 3H), 1.36-1.56 (m, 5H). MS (m/z) 415.

The following examples were synthesized in the same manner as the aboveexample.

MS Ex. Structure Name (M + H)⁺ NMR 80

N-(5-fluoro-1H- indazol-3-yl)-7- methyl-6-((4- methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin- 4-amine 455 ¹H NMR (400 MHz, DMSO-d6)Shift: 13.00 (s, 1H), 9.97 (s, 1H), 9.09 (s, 1H), 8.58 (d, J = 5.6 Hz,1H), 7.91 (s, 1H), 7.60 (dd, J = 9.2, 4.2 Hz, 1H), 7.48 (dd, J = 9.1,2.0 Hz, 1H), 7.32 (td, J = 9.1, 2.3 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H),3.84 (dd, J = 11.5, 4.2 Hz, 2H), 3.39-3.53 (m, 2H), 2.80 (s, 3H), 2.12(br. s., 2H), 1.38-1.55 (m, 5H) 81

N-(4,5-dimethyl-1H- pyrazol-3-yl)-7- ethyl-6-((4- methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin- 4-amine 429 ¹H NMR (400 MHz, DMSO-d6)Shift: 12.30 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.47 (d, J = 5.3 Hz,1H), 7.86 (s, 1H), 6.50 (d, J = 5.6 Hz, 1H), 3.82 (dd, J = 11.7, 4.4 Hz,2H), 3.44 (t, J = 11.4 Hz, 2H), 3.15 (q, J = 7.3 Hz, 2H), 2.21 (s, 3H),2.08 (td, J = 12.7, 4.9 Hz, 2H), 1.78 (s, 3H), 1.38-1.50 (m, 5H), 1.30(t, J = 7.3 Hz, 3H) 82

7-ethyl-N-(5-fluoro- 1H-indazol-3-yl)-6- ((4- methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin- 4-amine 469 ¹H NMR (400 MHz, DMSO-d6)Shift: 13.00 (s, 1H), 9.98 (s, 1H), 9.09 (s, 1H), 8.58 (d, J = 5.6 Hz,1H), 7.94 (s, 1H), 7.60 (dd, J = 9.1, 4.0 Hz, 1H), 7.48 (d, J = 9.1 Hz,1H), 7.28-7.37 (m, 1H), 7.11 (d, J = 5.3 Hz, 1H), 3.83 (d, J = 12.1 Hz,2H), 3.39-3.51 (m, 2H), 3.19 (d, J = 7.3 Hz, 2H), 2.08 (br. s., 2H),1.43 (s, 5H), 1.32 (t, J = 7.3 Hz, 3H) 83

N-(7-chloro-1H- indazol-3-yl)-7- methyl-6-((4- methyltetrahydro-2H-pyran-4- yl)sulfonyl)quinolin- 4-amine 471 ¹H NMR (400 MHz, DMSO-d6)Shift: 13.40 (br. s., 1H), 10.13 (br. s., 1H), 9.10 (s, 1H), 8.60 (br.s., 1H), 7.92 (br. s., 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.08-7.26 (m,2H), 3.77-3.91 (m, 2H), 3.40-3.53 (m, 2H), 2.80 (s, 3H), 2.08-2.17 (m,2H), 1.39-1.53 (m, 5H)

Pharmaceutical Compositions

Example A

Tablets are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound of Example 1  5 mgMicrocrystalline cellulose 100 mg Lactose 100 mg Sodium starchglycollate  30 mg Magnesium stearate  2 mg Total 237 mg

Example B

Capsules are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound of Example 3  15 mg Dried starch178 mg Magnesium stearate  2 mg Total 195 mg

Biological Assay:

A fluorescent polarization based binding assay was developed toquantitate interaction of novel test compounds at the ATP binding pocketof RIPK2, by competition with a fluorescently labeled ATP competitiveligand. Full length FLAG His tagged RIPK2 was purified from aBaculovirus expression system and was used at a final assayconcentration of twice the KDapparent. A fluorescent labeled ligand(5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid, prepared as described in WO2011/120025) was used at a final assayconcentration of 5 nM. Both the enzyme and ligand were prepared insolutions in 50 mM HEPES pH7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, and1 mM CHAPS. Test compounds were prepared in 100% DMSO and 100 mL wasdispensed to individual wells of a multiwell plate. Next, 5ul RIPK2 wasadded to the test compounds at twice the final assay concentration, andincubated at rt for 10 minutes. Following the incubation, 5 ul of thefluorescent labeled ligand solution, was added to each reaction, attwice the final assay concentration, and incubated at rt for at least 10minutes. Finally, samples were read on an instrument capable ofmeasuring fluorescent polarization.

Test compound inhibition was expressed as percent (%) inhibition ofinternal assay controls.

For concentration/dose response experiments, normalized data were fitand pIC₅₀s determined using conventional techniques. The pIC₅₀s areaveraged to determine a mean value, for a minimum of 2 experiments.

As determined using the above method, the compounds of Examples 1-83exhibited a pIC₅₀ between 5.0 and 9.0 e.g., for example, the compoundsof Example 1 and Example 74 inhibited RIP2 kinase in the above methodwith a mean pIC₅₀ of 8.2 and 8.6, respectively.

FLAG his Tagged RIPK2 Preparation:

Full-length human RIPK2 (receptor-interacting serine-threonine kinase 2)cDNA was purchased from Invitrogen (Carlsbad, Calif., USA, CloneID:IOH6368, RIPK2-pENTR 221). Gateway® LR cloning was used tosite-specifically recombine RIPK2 downstream to an N-terminal FLAG-6Hiscontained within the destination vector pDEST8-FLAG-His6 according tothe protocol described by Invitrogen. Transfection into Spodopterafrugiperda (Sf9) insect cells was performed using Cellfectin®(Invitrogen), according to the manufacturer's protocol.

Sf9 cells were grown in Excell 420 (SAFC Biosciences, Lenexa, Kans., US;Andover, Hampshire UK) growth media at 27° C., 80 rpm in shake flaskuntil of a sufficient volume to inoculate a bioreactor. The cells weregrown in a 50 litre working volume bioreactor (Applikon, Foster City,Calif., US; Schiedam, Netherlands) at 27° C., 30% dissolved oxygen andan agitation rate of 60-140 rpm until the required volume was achievedwith a cell concentration of approximately 3.7×e6 cells/mL. The insectcells were infected with Baculovirus at a multiplicity of infection(MOI) of 12.7. The cultivation was continued for a 43 hour expressionphase. The infected cells were removed from the growth media bycentrifugation at 2500 g using a Viafuge (Carr) continuous centrifuge ata flow rate of 80 litres/hour. The cell pellet was immediately frozenand subsequently supplied for purification.

Purification Procedure I: 9.83×10¹⁰ Insect cells were re-suspended in1.4 L lysis buffer (50 mM Tris (pH 8.0), 150 mM NaCl, 0.5 mM NaF, 0.1%Triton X-100, 1 mL/litre Protease Inhibitor Cocktail Set III (availablefrom EMD Group; CalBiochem/Merck Biosciences, Gibbstown, N.J., US;Damstadt, Germany) and processed by dounce homogenization on ice. Thesuspension was then clarified by centrifugation at 47,900 g for 2 hours,at 4° C. The lysate was decanted from the insoluble pellet and loaded ata linear flow rate of 16 cm/h onto a 55 mL FLAG-M2 affinity column(2.6×10.4 cm) that had been pre-equilibrated with 10 column volumesbuffer A (50 mM Tris (pH 8.0), 150 mM NaCl, 0.5 mM NaF, 1 mL/litreProtease Inhibitor Cocktail Set III). The column was then washed with 15column volumes buffer A, and eluted with 6 column volumes buffer B(buffer A+150 μg/mL 3×FLAG peptide) at a linear flow rate of 57 cm/h.Fractions identified by SDS-PAGE as containing protein of interest weredialyzed to remove the 3×FLAG peptide from the preparation against 5 Lof Buffer A (not containing the Protease Inhibitor Cocktail) overnight,using 10 kDa MWCO SnakeSkin Pleated Dialysis Tubing. The purificationprocess yielded 11.3 mg of total protein, with the RIPK2 present at 40%purity by gel densitometry scanning, and identity confirmed by peptidemass fingerprinting. The main contaminating proteins in the preparationwere identified as lower molecular weight degraded species of RIPK2.

Purification Procedure II: 100 g cells (10 liter scale fermentation)were frozen, thawed, and re-suspended in 1 L lysis buffer (50 mM TrisHCL pH7.5, 250 mM NaCl, 0.1 mM TCEP, 3 ml Protease inhibitor cocktail)and lysed by high pressure homogenization at 10,000 psi once (Avestin).The suspension was then clarified by centrifugation at 35,000 g for 45minutes at 4° C. The supernatant was collected by centrifugation andincubated with 5 ml anti-FLAG-M2 resin which was pre-equilibrated withbuffer A (50 mM Tris HCL pH7.5, 250 mM NaCl, 0.1 mM TCEP). After proteinbinding at 4 C degree for 1 hour, the resin was packed into two 25 mldisposable columns. Each column was washed with 25 ml buffer A andeluted with 10 ml (buffer A+200 ug/ml Flag peptide). The elution poolwas concentrated to 1 ml and applied to a superdex 200 (16/60) sizingcolumn. Fractions containing full length RIPK2 were collected accordingto SDS-PAGE analysis results. The purification process yielded 1.36 mg/L80% pure RIPK2 protein and identity was confirmed by peptide massfingerprinting.

Biological In Vivo Assay

The efficacy of RIP2 inhibitors may also be evaluated in vivo inrodents. Intraperitoneal (i.p.) or intravenous (i.v.) administration ofL18-MDP in mice has been shown to induce an inflammatory responsethrough activation of the NOD2 signaling pathway (Rosenweig, H. L., etal. 2008. Journal of Leukocyte Biology 84:529-536). The level of theinflammatory response in the L18-MDP treated mice/rats is monitoredusing conventional techniques by measuring increases in cytokine levels(IL8, TNFα, IL6 and IL-1β) in serum and/or peritoneal lavage fluid andby measuring neutrophil influx into the peritoneal space (when L18-MDPis dosed i.p.). Inhibition of the L18-MDP induced inflammatory responsein treated rodents may be shown by orally pre-dosing with selectedcompounds of this invention, then measuring and comparing cytokinelevels (IL8, TNFα, IL6 and IL-1β) in serum and/or peritoneal lavagefluid and neutrophil influx into the peritoneal space (when L18-MDP isdosed i.p.) using conventional techniques.

For example, rats (8 rats/dose group for each test or control compound)were orally pre-dosed with the compound of Example 1 at 0.01 to 30mg/kg, the compound of Example 5 at 0.01 to 10 mg/kg and a compound usedas a positive control (prednisolone and a reference compound, forExample 1 and Example 5, respectively), followed by dosing with L18-MDP(50 μg/rat) 0.25 hours after pre-dosing. Combined cytokine levels (IL8,TNFα, IL6 and IL-1β) in whole blood samples taken from the rats in thisstudy were measured using an antibody based detection (Meso-ScaleDiscovery platform). The combined cytokine response was calculated asthe averaged response for the 4 cytokines measured relative to theresponse observed in the vehicle (L18-MDP) treated mice, and is depictedin FIGS. 1 and 2 as the mean±standard error of the mean (n=8rats/group).

Additionally, the compound of Example 23 at 0.003 to 3 mg/kg, thecompound Example 31 at 0.03 to 30 mg/kg, and a reference compound usedas a positive control were orally pre-dosed in rats (8 rats/dose groupfor each test or control compound), followed by dosing with L18-MDP (50μg/rat) or vehicle 0.25 hours after pre-dosing. Cytokine levels (IL8) inwhole blood samples taken from the rats in this study were measuredusing an antibody based detection (Meso-Scale Discovery platform). Thecytokine response was calculated as a percentage relative to theresponse observed in the vehicle treated mice, and is depicted in FIGS.3 and 4 as the mean±standard error of the mean (n=8 rats/group).

1-36. (canceled)
 37. A compound according to Formula (I):

wherein: R¹ is H, —SO₂(C₁-C₄alkyl), —CO(C₁-C₄alkyl), or (C₁-C₄alkyl); R²is —SOR^(a) or —SO₂R^(a), wherein R^(a) is an optionally substituted(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 4-7 membered heterocycloalkyl, aryl, orheteroaryl group, wherein: said (C₁-C₆)alkyl is optionally substitutedby one or two groups each independently selected from the groupconsisting of cyano, hydroxyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl, —SO₂(C₁-C₄ alkyl),—CONH₂, —CONH(C₁-C₄ alkyl), —NHC(═O)(C₁-C₄ alkyl), —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C(═O)(C₁-C₄ alkyl)), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —NHSO₂(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(SO₂(C₁-C₄ alkyl)), amino, (C₁-C₄ alkyl)amino-,(C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, C₃-C₇cycloalkyl, phenyl, 5-6 memberedheteroaryl, 9-10 membered heteroaryl, 4-7 membered heterocycloalkyl and(phenyl)(C₁-C₄ alkyl)amino-, wherein said C₃-C₇cycloalkyl, phenyl,(phenyl)(C₁-C₄ alkyl)amino-, 5-6 membered heteroaryl, 9-10 memberedheteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by1-3 groups each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy, said(C₃-C₇)cycloalkyl or 4-7 membered heterocycloalkyl is optionallysubstituted by 1-3 groups each independently selected from the groupconsisting of halogen, —CF₃, hydroxyl, amino, (C₁-C₄ alkyl)amino-,(C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl-, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₂-C₄)alkoxy-, and said aryl or heteroaryl is optionallysubstituted by 1-3 groups each independently selected from the groupconsisting of halogen, —CF₃, hydroxyl, amino, (C₁-C₄)alkyl,phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy, and whereinsaid heteroaryl is a 5-6 membered heteroaryl or a 9-10 memberedheteroaryl, and any of said 4-7 membered heterocycloalkyl contains oneheteroatom selected from the group consisting of N, O and S, any of said5-6 membered heteroaryl contains one heteroatom selected from the groupconsisting of N, O and S and optionally further containing one or twonitrogen atoms, and any of said 9-10 membered heteroaryl contains oneheteroatom selected from the group consisting of N, O and S andoptionally further containing 1, 2 or 3 nitrogen atoms; R³ is halogen,hydroxy, (C₁-C₄)alkyl-, (C₁-C₄)alkoxy-, halo(C₁-C₄)alkyl-,halo(C₁-C₄)alkoxy-, (C₁-C₄)alkoxy(C₁-C₆)alkyl-,halo(C₁-C₄)alkoxy(C₁-C₆)alkyl-, (C₁-C₄)alkoxy(C₂-C₆)alkoxy-,halo(C₁-C₄)alkoxy(C₂-C₆)alkoxy-, hydroxy(C₁-C₄)alkyl-,hydroxy(C₂-C₆)alkoxy-, cyano(C₁-C₄)alkyl-, cyano(C₂-C₆)alkoxy-, or(C₃-C₆)cycloalkoxy-, wherein the halo(C₁-C₄)alkyl-, halo(C₁-C₄)alkoxy-,halo(C₁-C₄)alkoxy(C₁-C₆)alkyl-, or halo(C₁-C₄)alkoxy(C₂-C₆)alkoxy-contains 2 or 3 halo atoms and wherein the (C₃-C₆)cycloalkyl moiety ofthe (C₃-C₆)cycloalkoxy- group, is optionally substituted by a groupselected from the group consisting of cyano, halo, hydroxyl,(C₁-C₆)alkoxy and (C₁-C₄)alkoxy(C₂-C₆)alkoxy; Z is phenyl oraryl(C₁-C₄)alkyl-, substituted by R⁴, R⁵, R⁶ and R⁷, wherein: R⁴ is H,halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, or aminocarbonyl,wherein the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy- isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; and each of R⁵, R⁶ and R⁷ is independently selected fromthe group consisting of H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; or Z is phenyl substituted by R⁸, R⁹ andR¹⁰, wherein: R⁸ and R⁹ are located on adjacent atoms and taken togetherwith the atoms to which they are attached form a 5-membered heterocyclicgroup containing 1, 2 or 3 heteroatoms each independently selected fromthe group consisting of N, O and S, which 5-membered heterocyclic groupis substituted by R¹¹; wherein one of R¹⁰ or R¹¹ is H, halogen, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, or aminocarbonyl,where the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; and the other of R¹⁰ or R¹¹ is H, hydroxyl, halogen,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; orZ is pyrazolyl, having the formula:

wherein: R¹² is methyl or trifluoromethyl (—CH₃ or —CF₃); R¹³ is H,methyl, hydroxymethyl, or trifluoromethyl (—CH₃, —CH₂OH or —CF₃); R¹⁴ isH or (C₁-C₃)alkyl; or R¹² and R¹³, taken together with the atoms towhich they are attached, form a 6 membered carbocyclic ring orheterocyclic ring substituted by R¹⁵ and R¹⁶, wherein the heterocyclicring contains 1 nitrogen atom; wherein R¹⁵ and R¹⁶ are eachindependently selected from the group consisting of H, halogen, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, and aminocarbonyl,wherein the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; provided that the compound is notN-(4-chloro-2-fluorophenyl)-7-methoxy-6-[(2-methoxyethyl)sulfinyl]-4-quinolinamineor 3-[[7-bromo-6-(methylsulfonyl)-4-quinolinyl]amino]-4-methyl-phenol;or a salt thereof.
 38. The compound or salt according to claim 37,wherein Z is phenyl, having the formula:

wherein: R^(Z1) is H, halogen, —CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxy;R^(Z2) is H, H halogen, —CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; R^(Z3) isH, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and R^(Z4) is hydroxyl,hydroxy(C₁-C₄)alkyl or (C₁-C₄)alkoxy.
 39. The compound or salt accordingto claim 37, wherein Z is benzothiazolyl, optionally substituted by for2 substituents each independently selected from the group consisting ofhalogen, (C₁-C₄)alkyl, —CF₃, and (C₁-C₄)alkoxy.
 40. The compound or saltaccording to claim 37, wherein Z is pyrazolyl, R¹² and R¹³ areindependently selected from the group consisting of methyl andtrifluoromethyl, and R¹⁴ is H or methyl.
 41. The compound or saltaccording to claim 37, wherein Z is pyrazolyl, R¹² is methyl, R¹³ ismethyl or trifluoromethyl, and R¹⁴ is H.
 42. The compound or saltaccording to claim 37, wherein Z is pyrazolyl, substituted by R¹² andR¹³ wherein R¹² and R¹³ are located on adjacent carbon atoms and takentogether with the atoms to which they are attached form a 6 memberedcarbocyclic ring or heterocyclic ring substituted by R¹⁵ and R¹⁶;wherein R¹⁵ is H, halogen, cyano, (C₁-C₄)alkyl, —CF₃, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and R¹⁶ is H, H hydroxyl, halogen, —CF₃,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or (C₁-C₄)alkoxy.
 43. The compound orsalt according to claim 37, wherein Z is an optionally substitutedindazolyl or pyrazolo[3,4-b]pyridinyl group, where the Z group isoptionally substituted by 1 or 2 substituents each independentlyselected from the group consisting of chloro, fluoro, methyl, andmethoxy.
 44. The compound or salt according to claim 37, wherein R¹ isH.
 45. The compound or salt according to claim 37, wherein R² is or—SO₂R^(a).
 46. The compound or salt according to claim 37, wherein R^(a)is (C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl is optionally substituted byfor 2 substituents each independently selected from the group consistingof hydroxyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino, (C₁-C₄alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, (phenyl)(C₁-C₄alkyl)amino-, —CO₂ (C₁-C₄)alkyl, —CONH₂, —SO₂(C₁-C₄)alkyl, and aC₃-C₆cycloalkyl, phenyl, 4-6-membered heterocycloalkyl, 5-6-memberedheteroaryl, or 9-10-membered heteroaryl, where said C₃-C₆cycloalkyl,phenyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, or9-10-membered heteroaryl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl-and (C₁-C₄)alkoxy.
 47. The compound or salt according to claim 37,wherein R^(a) is (C₁-C₄)alkyl wherein said (C₁-C₄)alkyl is optionallysubstituted by a substituent selected from the group consisting ofhydroxyl, (C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-, amino, (C₁-C₃alkyl)amino-, and (C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-.
 48. The compound orsalt according to claim 37, wherein R^(a) is C₃-C₆cycloalkyl,4-6-membered heterocycloalkyl, 5-6-membered heteroaryl or phenyl,wherein said C₃-C₆cycloalkyl, 4-6-membered heterocycloalkyl,5-6-membered heteroaryl or phenyl is optionally substituted by 1-3groups each independently selected from the group consisting of halogen,—CF₃, hydroxyl, amino, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy.
 49. The compound or saltaccording to claim 37, wherein R^(a) is (C₁-C₄)alkyl, tetrahydrofuranyl,tetrahydropyranyl or piperidinyl, wherein: said (C₁-C₄)alkyl isoptionally substituted by a substituent selected from the groupconsisting of hydroxyl, (C₁-C₂)alkoxy, (C₁-C₂)alkoxy(C₂-C₃)alkoxy-,amino, (C₁-C₃ alkyl)amino-, (C₁-C₃ alkyl)(C₁-C₂ alkyl)amino-, and aC₃-C₆cycloalkyl (optionally substituted by (C₁-C₄)alkyl orhydroxy(C₁-C₄)alkyl), and said tetrahydrofuranyl, tetrahydropyranyl orpiperidinyl is optionally substituted by 1 or 2 groups independentlyselected from the group consisting of halogen, —CF₃, hydroxyl, amino,(C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and(C₁-C₄)alkoxy.
 50. The compound or salt according to claim 37, whereinR^(a) is an unsubstituted (C₁-C₄)alkyl or a (C₁-C₄)alkyl substituted byone substituent selected from the group consisting of hydroxyl,(C₁-C₂)alkoxy, and (C₁-C₂)alkoxy(C₂-C₃)alkoxy-.
 51. The compound or saltaccording to claim 37, wherein R^(a) is tetrahydropyranyl, wherein thetetrahydropyranyl group is optionally substituted by 1 or 2independently selected (C₁-C₄)alkyl groups.
 52. The compound or saltaccording to claim 37, wherein R³ is halogen, hydroxy, (C₁-C₄)alkyl-,halo(C₁-C₄)alkyl-, (C₁-C₄)alkoxy-, halo(C₁-C₄)alkoxy-,(C₁-C₄)alkoxy(C₁-C₆)alkyl-, (C₁-C₄)alkoxy(C₂-C₆)alkoxy-,hydroxy(C₁-C₄)alkyl-, or hydroxy(C₂-C₆)alkoxy-.
 53. The compound or saltaccording to claim 37, wherein R³ is halogen, hydroxy, (C₁-C₃)alkyl-,halo(C₁-C₂)alkyl-, (C₁-C₃)alkoxy-, (C₁-C₃)alkoxy(C₁-C₃)alkyl-,(C₁-C₃)alkoxy(C₂-C₃)alkoxy-, hydroxy(C₁-C₃)alkyl-, orhydroxy(C₂-C₃)alkoxy-.
 54. A compound which is:6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfinyl)-4-quinolinamine;6-[(1,1-dimethylethyl)sulfinyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(methyloxy)-4-quinolinamine;2-((4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-7-methoxyquinolin-6-yl)sulfonyl)-2-methylpropan-1-ol;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;2-((4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-7-methylquinolin-6-yl)sulfonyl)ethanol;N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)-7-methoxyquinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-((2-methoxyethyl)sulfonyl)quinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxy-6-(3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)-7-methoxyquinolin-4-amine;6-(tert-butylsulfonyl)-N-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-methoxyquinolin-4-amine;N-[4-chloro-3-(methyloxy)phenyl]-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;N-[4-chloro-3-(methyloxy)phenyl]-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4-quinolinamine;N-1,3-benzothiazol-5-yl-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4-quinolinamine;2-{[4-{[4-chloro-3-(methyloxy)phenyl]amino}-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol;N-(5-fluoro-1H-indazol-3-yl)-7-(methyloxy)-6-(tetrahydro-2H-pyran-4-ylsulfonyl)-4-quinolinamine;2-{[4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol;N-[4-chloro-3-(methyloxy)phenyl]-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;N-1,3-benzothiazol-5-yl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;N-(5-fluoro-1H-indazol-3-yl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;2-{[4-(1,3-benzothiazol-5-ylamino)-7-(methyloxy)-6-quinolinyl]sulfonyl}ethanol;6-(isopropylsulfonyl)-7-methoxy-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)quinolin-4-amine;6-(tert-butylsulfonyl)-7-methoxy-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)quinolin-4-amine;6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethoxyquinolin-4-amine;6-(tert-butylsulfonyl)-7-ethoxy-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine;7-chloro-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;7-chloro-N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(5-fluoro-1H-indazol-3-yl)-7-methyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)-7-(trifluoromethyl)quinolin-4-amine;6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-(trifluoromethyl)quinolin-4-amine;6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;6-(tert-butylsulfonyl)-7-chloro-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine;6-(tert-butylsulfonyl)-7-ethyl-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine;N-(5-fluoro-1H-indazol-3-yl)-6-(isopropylsulfonyl)-7-methylquinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-(isopropylsulfonyl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethylquinolin-4-amine;7-ethyl-N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethyl-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;(3-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methylphenyl)methanol;7-ethoxy-N-(5-fluoro-1H-indazol-3-yl)-6-(isopropylsulfonyl)quinolin-4-amine;N-(7-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;6-(tert-butylsulfonyl)-N-(7-fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;6-(tert-butylsulfonyl)-N-(5,7-difluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;6-(tert-butylsulfonyl)-N-(6,7-difluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;6-(tert-butylsulfonyl)-N-(7-chloro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine;6-(tert-butylsulfonyl)-7-methoxy-N-(5-methoxy-1H-indazol-3-yl)quinolin-4-amine;6-(tert-butylsulfonyl)-N-(7-fluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(5,7-difluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(5-methoxy-1H-indazol-3-yl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(6,7-difluoro-1H-indazol-3-yl)-7-methylquinolin-4-amine;6-(tert-butylsulfonyl)-N-(7-chloro-1H-indazol-3-yl)-7-methylquinolin-4-amine;7-methoxy-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(5,7-difluoro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(4-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(6-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(6,7-difluoro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;7-methoxy-N-(5-methoxy-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(5-chloro-1H-indazol-3-yl)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(7-chloro-1H-indazol-3-yl)-7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-1,3-benzothiazol-5-yl-6-(methylsulfonyl)-4-quinolinamine;7-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;7-bromo-6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine;7-bromo-N-(4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;7-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-(isopropylsulfonyl)quinolin-4-amine;7-bromo-N-(5-fluoro-1H-indazol-3-yl)-6-(isopropylsulfonyl)quinolin-4-amine;7-bromo-N-(5-fluoro-1H-indazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)-4-quinolinamine;6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-ol;2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinolin-7-yl)oxy)ethanol;6-(tert-butylsulfonyl)-7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinolin-4-amine;7-(difluoromethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethanol;(3-((6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)amino)-4-methyl-1H-pyrazol-5-yl)methanol;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(5-fluoro-1H-indazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;7-ethyl-N-(5-fluoro-1H-indazol-3-yl)-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;N-(7-chloro-1H-indazol-3-yl)-7-methyl-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-amine;or a salt thereof.
 55. A pharmaceutical composition comprising thecompound according to claim 37, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.
 56. A method oftreating a RIP2 kinase-mediated disease or disorder which comprisesadministering a therapeutically effective amount of the compoundaccording to claim 37, or a pharmaceutically acceptable salt thereof, toa human in need thereof, wherein said RIP2 kinase-mediated disease ordisorder is selected from the group consisting of uveitis, interleukin-1converting enzyme associated fever syndrome, dermatitis, acute lunginjury, type 2 diabetes mellitus, arthritis, ulcerative colitis, Crohn'sdisease, early-onset inflammatory bowel disease, extra-intestinalinflammatory bowel disease, non-alcohol steatohepatitis, alcoholsteatohepatitis, autoimmune hepatitis, asthma, graft versus hostdisease, systemic lupus erythematosus, multiple sclerosis, sarcoidosis,Blau syndrome, early-onset sarcoidosis, Wegner's granulomatosis,interstitial pulmonary disease and prevention of ischemia reperfusioninjury in a solid organ in response ischemia induced by cardiac surgery,organ transplant and sepsis.